[XLS] · Web viewMice "preconditioned" with latrepirdine show a delayed symptom onset and a...

ID Catalog NO Name Alternative Names CAS SMILES MW Target1 HY-19312 3-Methyladen3-MA 5142-23-4 NC1=C2N=C149.1533 Autophagy; P2 HY-15027 5-AminosalicyMesalamine; 89-57-6 OC1=C(C(O) 153.1354 JNK; p38 MA3 HY-17471A Metformin (h1,1-Dimethyl1115-70-4 NC(NC(N(C)C165.6246 AMPK; Autop4 HY-77195 Poloxime 2,5-Cyclohex17302-61-3 CC1=CC(C(C179.2157 Polo-like Kin5 HY-15644 AG 18 RG-50810;Ty118409-57-7 N#C/C(C#N) 186.1668 EGFR6 HY-N0342 Scopoletin Gelseminic a92-61-5 O=C1C=CC2=192.1681 NF-κB; p38 7 HY-78263 MNS NSC 170724;51485-00-3 O=[N+]([O- 193.1562 Src; Syk8 HY-B1016 Trapidil AR-12008 15421-84-8 CC1=NC2=NC205.2596 PDGFR9 HY-12239 CID755673 CID 755673; 521937-07-5 O=C1NCCCC217.2206 PKD

10 HY-12041 SP600125 SP 600125;S 129-56-6 O=C1C2=C3220.2261 Autophagy; J11 HY-101032 RIPA-56 RIPA56;RIPA 1956370-21- CCC(C)(C)C 221.29546 RIP kinase12 HY-11012 TDZD-8 TDZD 8;TDZD8327036-89-5 O=C(N1CC2=222.2636 GSK-313 HY-13802 SC-514 GK 01140;SC354812-17-2 O=C(C1=C(N224.3026 IKK14 HY-16561 Resveratrol trans-Resvera501-36-0 OC1=CC=C(/228.2433 Autophagy; I15 HY-10374 SU5416 Semaxinib;S 204005-46-9 O=C(NC1=CC238.28446 VEGFR16 HY-B0923 Danthron Dantron;Chry117-10-2 O=C1C2=C(C240.2109 AMPK17 HY-18629 SU9516 SU-9516 377090-84-1 O=C1NC2=C(241.2453 Autophagy; 18 HY-16397A Phenformin (Phenethylbig834-28-6 NC(NC(NCCC241.7205 AMPK19 HY-10520 CGP 57380 CGP57380;C 522629-08-9 NC1=NC=NC244.2278 MNK20 HY-13518 Piceatannol Astringenin;t10083-24-6 OC1=CC=C(/244.2427 Autophagy; 21 HY-100233 IQ-1S (free a IQ 1S free ac23146-22-7 O/N=C1C2= 247.2515 JNK22 HY-19316 NU2058 NU-2058;O6-161058-83-9 NC1=NC(OC 247.2963 CDK23 HY-15338 TG003 TG 003;TG-0 719277-26-6 CC(/C=C1SC 249.3287 CDK24 HY-13461A PHA-767491 (CAY-10572 hy942425-68-5 O=C1C2=C(N249.6962 CDK25 HY-15528 kb NB 142-7 kb-NB142-701233533-04- O=C1NCCSC 251.3247 PKD26 HY-100463 TPI-1 TPI 1;TPI1 79756-69-7 ClC1=CC(C2 253.0808 Discoidin Do27 HY-10519 BMS-345541 (BMS345541 (f445430-58-0 CC1=CN=C2C255.3183 IKK28 HY-N0235 Bakuchiol (S)-(+)-Bakuc10309-37-2 OC1=CC=C(/256.3826 p38 MAPK29 HY-10109 AS-605240 AS605240;AS648450-29-7 O=C(NC/1= 257.2679 Autophagy; P30 HY-13417 AICAR Acadesine;AI2627-69-2 OC[C@@H]1[258.2313 AMPK; Autop31 HY-15760 Necrostatin- Necrostatin 4311-88-0 O=C(C(CC1=259.3268 Autophagy; R32 HY-101947 SMI-16a PIM1/2 Kinase587852-28-6 O=C(NC/1=O263.31222 Pim33 HY-18982 Anisomycin Flagecidin;W 22862-76-6 O[C@@H]1[C265.305 Bacterial; JN34 HY-N0003 Honokiol NSC 293100;35354-74-6 OC1=C(CC=C266.3343 Akt; Autopha35 HY-12028 PD98059 PD 98059;PD167869-21-8 O=C1C=C(O 267.2793 Autophagy; 36 HY-N0183 Formononeti Biochanin B; 485-72-3 O=C1C(C2=C268.2641 FGFR37 HY-N1201 Apigenin 4',5,7-Trihyd 520-36-5 OC1=C2C(OC270.2369 Autophagy; I38 HY-14393 Emodin Frangula em 518-82-1 O=C1C2=C(C270.2369 Autophagy; C39 HY-14596 Genistein NPI 031L 446-72-0 OC1=C2C(OC270.2369 Autophagy; 40 HY-15900 SAR245409 Voxtalisib;X 934493-76-2 O=C1C(C2=N270.2899 mTOR; PI3K41 HY-16558 Butein 2’,3,4,4’-te 487-52-5 OC1=CC=C(C272.2528 Autophagy; 42 HY-12524 Bikinin Abrasin 188011-69-0 O=C(O)CCC( 273.0834 GSK-3

43 HY-16576 TCS-PIM-1-4aSMI-4a;SMI 4327033-36-3 O=C(NC/1=O273.231 Pim44 HY-101426 RG14620 RG 14620;RG136831-49-7 N#C/C(C1=C275.13272 EGFR45 HY-18314 GW 441756 GW441756;G504433-23-2 O=C1/C(C2=275.3046 Trk Receptor46 HY-15513 TC-DAPK 6 DAPK inhibito315694-89-4 O=C(OC(/C=276.2894 DAPK47 HY-19832 SC66 SC-66;SC 66 871361-88-5 O=C1/C(CCC276.3324 Akt48 HY-19807 Indirubin-3' Indirubin-3'- 160807-49-8 O=C1NC2=C(277.2774 GSK-349 HY-10074 TPCA-1 TPCA 1 507475-17-4 FC1=CC=C(C279.2901 IKK50 HY-19341 Compound 4 Compound-4 168425-64-7 O=C1C=C(N 281.3092 DNA-PK51 HY-13804 PP1 AGL 1872;EI 172889-26-8 NC1=C2C(N(281.3556 Src52 HY-13842 BX517 BX-517;BX 5 850717-64-5 NC(NC1=CC=282.2973 PDK-153 HY-15511 Tyrphostin A AG 17; Tyrph10537-47-0 N#C/C(C#N)=282.3801 VEGFR54 HY-12444 Y15 FAK inhibitor 4506-66-5 [H]Cl.[H]Cl. 284.0142 FAK55 HY-N0400 Wogonin 632-85-9 O=C1C=C(C2284.2635 Autophagy; 56 HY-N0176 Dihydroartemβ-Dihydroart 71939-50-9 O[C@@H]1[[email protected] JNK; NF-κB57 HY-N0752 Scutellarein 6-Hydroxyapi529-53-3 O=C1C=C(C2286.2363 Autophagy; S58 HY-13777A Zoledronic a Zoledronate 165800-06-6 OC(P(O)(O)=290.1049 Autophagy; 59 HY-10518 BMS-345541 BMS345541 h547757-23-3 CC1=CN=C2C291.7792 IKK60 HY-15217 CHR-6494 CHR 6494;C 1333377-65- CCCNC(C=C 292.3384 Haspin Kinas61 HY-13275 IRAK inhibito 2-Pyridinamin1042224-63- C1(C2=CN= 293.3663 IRAK62 HY-12000 AG-490 AG 490;Tyrp 133550-30-8 OC1=C(C=CC294.3047 Autophagy; 63 HY-14615 [6]-Gingerol (S)-(+)-[6]Gi 23513-14-6 CCCCC[C@H]294.3859 AMPK; Apopto64 HY-10407 SU 5402 SU-5402;SU5215543-92-3 O=C(CCC1=C296.3205 FGFR; VEGFR65 HY-12134 Poloxin 321688-88-4 O=C(C(C(C) 297.3484 Polo-like Kin66 HY-12511 SKF-86002 72873-74-6 FC1=CC=C(C297.35 p38 MAPK67 HY-15838 ID-8 ID 8;ID8 147591-46-6 OC1=CC2=C(298.2934 DYRK68 HY-B0713 Amlexanox AA673;Amox68302-57-8 O=C(C1=C(N298.2934 IKK69 HY-13520 Nocodazole Oncodazole; 31430-18-9 O=C(OC)NC1301.3204 Autophagy; B70 HY-13805 PP2 AGL 1879;PP 172889-27-9 NC1=C2C(N(301.774 Src71 HY-18085 Quercetin 117-39-5 OC1=C(C2=C302.2357 Autophagy; PI72 HY-13822 SKI II SKI-II 312636-16-1 OC1=CC=C(N302.7786 SPHK73 HY-19625 MCB-613 MCB 613;MC 1162656-22- O=C1/C(CC( 304.3856 Src74 HY-10253 AG1024 AG-1024;Tyr 65678-07-1 N#C/C(C#N)=305.1698 Autophagy; I75 HY-13532 AS-252424 AS 252424;A900515-16-4 O=C(NC/1=O305.281 PI3K76 HY-100791 NSC23005 (sNSC 23005 s 1796596-46- O=C([O-])C 305.33 CDK77 HY-13276 IRAK inhibito Phenol, 4-[6- 928333-30-6 OC1=CC=C( 306.3187 IRAK78 HY-10108 LY294002 NSC 697286;154447-36-6 O=C1C=C(O 307.3432 Autophagy; C79 HY-13911 HydroxyfasudHA-1100;HA 105628-72-6 O=C1NC=CC307.3681 ROCK80 HY-10512 AR-A014418 AR-AO 14418487021-52-3 O=C(NCC1=C308.3131 GSK-381 HY-100023 LY3177833 LY-3177833; 1627696-51- O=C1N[C@@]309.2978 CDK82 HY-13328 INK-128 Sapaniserti 1224844-38- NC1=NC=NC2309.3259 Autophagy; 83 HY-10517 TSU-68 SU 6668;TSU252916-29-3 CC1=C(/C=C310.3471 PDGFR84 HY-12774 IC261 IC-261;SU-5 186611-52-9 O=C1NC2=C(311.3319 Casein Kinas85 HY-13257 Thiazovivin 1226056-71- O=C(C1=CS 311.3616 ROCK

86 HY-16071 AT13148 AT 13148;AT 1056901-62- ClC1=CC=C(313.7814 Akt87 HY-19805 STO-609 STO609;ST O52029-86-4 O=C(C1=C2 314.2943 CaMK88 HY-13524 AG-1478 Tyrphostin 153436-53-4 COC1=CC2=N315.7543 Autophagy; 89 HY-N0776 Isorhamnetin3'-Methylque480-19-3 O=C1C(O)=C316.2623 MEK; PI3K90 HY-20878 Tyrphostin A 148741-30-4 S=C(N)/C(C#316.461 EGFR; Trk Re91 HY-15704 LH846 LH 846;LH-8 639052-78-1 O=C(NC1=NC316.8052 Casein Kinas92 HY-13941 1-Naphthyl P1-NA-PP 1 221243-82-9 CC(N1N=C(C317.3877 Src93 HY-10590 TWS119 TWS 119;TW 601514-19-6 OC1=CC=CC(318.3293 Autophagy; 94 HY-10372 PP121 PP 121;PP-121092788-83- NC1=C2C(C3319.3638 mTOR; PDGF95 HY-12794 Vps34-PIK-III 1383716-40- NC1=NC=C(C319.3638 Autophagy; P96 HY-10583 Y-27632 (dih Y 27632 dihy129830-38-2 O=C([C@@H]1320.2579 ROCK97 HY-15457 Triciribine API-2;NSC 1 35943-35-2 OC[C@H]1OC320.304 Akt; DNA/RNA98 HY-13944 SKLB1002 SKLB 1002;S 1225451-84- CC1=NN=C(S320.39 VEGFR99 HY-18008 PS-1145 PS1145;PS 1 431898-65-6 O=C(C1=CC 322.7484 IKK

### HY-B0405A Bupivacaine (hydrochlorid18010-40-7 O=C(C1N(CC324.8887 Ribosomal S6### HY-15260A XL413 (hydroXL-413 hydro1169562-71- ClC1=CC=C2326.1779 CDK### HY-15755 RKI-1447 RKI 1447;RK 1342278-01- O=C(NC1=NC326.373 ROCK### HY-12302 Kenpaullone 9-Bromopaul142273-20-9 O=C1NC2=CC327.1754 CDK; GSK-3### HY-12275 FR 180204 FR180204;FR865362-74-9 NC1=NNC2=327.3427 ERK### HY-10341 Fasudil (HydrHA-1077;AT-8105628-07-7 O=S(C1=CC=327.8296 Autophagy; ### HY-18609 PD158780 PD-158780 171179-06-9 CNC1=CC2=C330.1826 EGFR### HY-15479 TTP 22 TTP22;TTP-2 329907-28-0 O=C(O)CCSC330.4246 Casein Kinas### HY-10295 SB 202190 SB202190;SB152121-30-7 FC1=CC=C(C331.343 Autophagy; ### HY-13942 1-NM-PP1 PP1 Analog I 221244-14-0 CC(N1N=C(C331.4142 CDK### HY-10339 KW-2449 KW 2449;KW1000669-72- O=C(C1=CC=332.399 FLT3### HY-15881 TCS JNK 5a JNK Inhibitor 312917-14-9 O=C(C1=C2C332.4189 JNK### HY-13718 Oglufanide H-Glu-Trp-OH38101-59-6 O=C(O)[[email protected] VEGFR### HY-12036 GSK1059615GSK 1059615958852-01-2 O=C(S/C1=C333.3638 mTOR; PI3K### HY-13785 ZM 306416 CB 676475;Z690206-97-4 COC1=CC2=N333.7447 Bcr-Abl; Src### HY-50864 GDC-0879 GDC0879;GD905281-76-7 O/N=C1C(C=334.3718 Raf### HY-14872 Tideglusib NP-12;NP031865854-05-3 O=C(N(SC1 334.3917 GSK-3### HY-15437 SL327 SL 327;SL-32305350-87-2 FC(F)(F)C1 335.3468 MEK### HY-12070 DPH 484049-04-9 O=C1NC(C(N336.3198 Bcr-Abl### HY-16962 CC-115 1228013-15- O=C1CN=C2C336.3512 DNA-PK; mT### HY-12059 AT7867 AT-7867;AT 857531-00-1 ClC1=CC=C(337.8459 Akt### HY-100673 LM22A-4 LM 22A4 37988-18-4 O=C(C1=CC(339.3438 Trk Receptor### HY-10371 Pim1/AKK1-I LKB1/AAK1 dua1093222-27- N#CC1=CC=C339.3501 Pim### HY-15456 NVP-BVU972 NVP-BVU 9721185763-69- CN1N=CC(C 340.3812 c-Met/HGFR### HY-12974 PRT-060318 PRT318 1194961-19- O=C(C1=CN=340.4228 Syk### HY-101611 MSC2530818 1883423-59- O=C(N1[[email protected] CDK### HY-13686 PQ401 PQ 401;PQ-4 196868-63-0 O=C(NC1=CC341.7915 IGF-1R### HY-13260 CCT128930 CCT 128930;885499-61-6 ClC1=CC=C(341.8379 Akt; Autopha### HY-12005 Fingolimod ( FTY720;FTY 162359-56-0 OCC(N)(CO) 343.9318 SPHK

AG 879；AG-879；AG879

### HY-12357 ETC-1002 ESP-55016;B 738606-46-7 O=C(O)C(C)(344.4861 AMPK### HY-15275 BMS-265246 BMS265246; 582315-72-8 CC1=CC(F)=345.3433 CDK### HY-15599 SSR128129E SSR;SSR-128848318-25-2 O=C([O-])C 346.3125 FGFR### HY-10111 TG100-115 TG100115;TG677297-51-7 NC1=C(C(N=346.3428 PI3K### HY-15154 NG 52 Compound 5 212779-48-1 ClC1=CC(NC 346.8147 CDK### HY-12787 L-779450 303727-31-3 OC1=CC(C2=347.7977 Autophagy; R### HY-N0865 Ingenol (-)-Ingenol 30220-46-3 O[C@@]([[email protected] PKC### HY-11002 CP-466722 CP466722;CP1080622-86- NC1=NC(C2 349.3467 ATM/ATR### HY-13949 SRPIN340 SRPIN 340;SR218156-96-8 O=C(NC1=CC349.3502 SRPK### HY-50855 CX-4945 Silmitaserti 1009820-21- O=C(C1=CC=349.7705 Autophagy; C### HY-15663 IPA-3 IPA 3;IPA3 42521-82-4 OC1=CC=C2350.4539 PAK### HY-100114 TA-01 TA01;TA 01 1784751-18- FC(C=C1)=C351.3246 Casein Kinas### HY-12529 Ro-3306 872573-93-8 O=C1N=C(N 351.4453 CDK### HY-13941B 1-Naphthyl P1-NA-PP 1 hy956025-47-1 CC(N1N=C(C353.8486 Src### HY-16585 VS-5584 SB-2343;VS51246560-33- NC1=NC=C(C354.4096 PI3K### HY-30237 Roscovitine CYC202; R-ros186692-46-6 OC[C@H](NC354.4493 CDK### HY-101443 ISCK03 ISCK 03;ISCK945526-43-2 O=S(C1=CC=355.45394 c-Kit### HY-N0736 Coptisine (chloride) 6020-18-4 C1(C(CC[N+ 355.7718 ROCK### HY-11009 CGP60474 CGP-60474;C164658-13-3 ClC1=CC(NC 355.8214 PKC### HY-10580 BIO 6BIO;6-BIO;G667463-62-9 O/N=C(C1=C356.1735 CDK; GSK-3### HY-13417A AICAR (phospAcadesine ph681006-28-0 OC[C@@H]1[356.2264 AMPK; Autop### HY-19957 CH5183284 Debio 1347; 1265229-25- O=C(C1=C(N356.3806 FGFR### HY-13737 R1530 R 1530;R-15 882531-87-5 CC(NN1)=C2356.7814 VEGFR### HY-18965 TAS-301 193620-69-8 O=C1NC2=C(357.4019 PKC### HY-15458 SAR131675 SAR-131675;1433953-83- O=C1C(C(NC358.3917 VEGFR### HY-12019 SGX-523 SGX523;SGX 1022150-57- CN1N=CC(C 359.4077 c-Met/HGFR### HY-15438 SB 415286 SB-415286;S264218-23-7 O=C(C(NC1=359.7207 GSK-3### HY-18009 LFM-A13 244240-24-2 BrC1=C(NC(/360.0014 Btk; Polo-lik### HY-14346 PD153035 ZM 252868;A153436-54-5 COC1=C(C=C360.2053 EGFR### HY-10578 PD 169316 PD169316;PD152121-53-4 FC(C=C1)=C360.3412 Autophagy; ### HY-50662 A-769662 A769662;A 7844499-71-4 N#CC1C(C2 360.3859 AMPK### HY-13907 TCS 359 TCS359;TCS-301305-73-7 O=C(C1=C(N360.4274 FLT3### HY-19836 PF06650833 PF-066508331817626-54- NC(C1=C(OC361.3675 IRAK### HY-11001 PHA-793887 PHA 793887 718630-59-2 CC(C)CC(NC 361.4818 CDK### HY-16708A ZLN024 (hydrZLN-024 hydrochloride CC1=CC=C(O361.6851 AMPK### HY-10992 AZD-7762 AZD7762;AZ 860352-01-8 O=C(N[C@@H362.4218 Checkpoint K### HY-12285 MLN1117 INK1117;MLN1268454-23- O=C(C1=CN=363.37 PI3K### HY-13946 BML-277 Chk2 Inhibit 516480-79-8 ClC(C=C1)= 363.7971 Checkpoint K### HY-13033 CDK-IN-2 CDK inhibitor 1269815-17- FC1=CC(C2=363.8138 CDK### HY-15193 EMD638683 EMD 638683 1181770-72- CC1=C(CC)C364.3433 SGK### HY-15294 CZC24832 CZC 24832;C1159824-67- FC1=CC(C2=364.3979 PI3K### HY-10114 TGX-221 TGX221;TGX 663619-89-4 O=C1N2C(C(364.4409 PI3K### HY-18749 SC79 SC-79 305834-79-1 O=C(OCC)C( 364.7803 Akt

### HY-18990 GSK180736AGSK 180736A817194-38-0 CC(N1)=C(C 365.3611 ROCK### HY-10917 GW2580 GW-2580 870483-87-7 NC1=NC(N)=366.4137 c-Fms### HY-15473 MLN120B ML120B;MLN783348-36-7 O=C(C1=CC=366.801 IKK### HY-18086 TCS PIM-1 1 SC 204330;T 491871-58-0 OC1=C(C(N2367.1961 Pim### HY-16291 APTO-253 LOR-253;LT- 916151-99-0 CC(N1)=C(C 367.3784 PAK### HY-N0052A Sanguinarine Pseudocheler5578-73-4 C[N+]1=CC2367.7825 Autophagy; ### HY-19713 LJI308 LJI 308;LJI-3 1627709-94- OC1=C(F)C=368.3766 Ribosomal S6### HY-11068 SB 239063 SB-239063;S193551-21-2 COC1=NC=CC368.4048 p38 MAPK### HY-14731 VE-821 VE821;VE 821232410-49- O=C(NC1=CC368.4096 ATM/ATR### HY-13896 PD168393 PD-168393;P194423-15-9 C=CC(NC1=C369.2153 Autophagy; ### HY-50686 Tivantinib ARQ197;ARQ905854-02-6 O=C(NC1=O 369.4159 c-Met/HGFR### HY-10337 Brivanib BMS-540215 649735-46-6 FC1=C(OC2=370.3776 Autophagy; ### HY-100550 MSDC 0160 MSDC-0160;M146062-49-9 O=C(N1)SC( 370.4222 Insulin Recep### HY-15878 LDC000067 LDC067;LDC 1073485-20- O=S(CC1=CC370.4255 CDK### HY-12012 SB 216763 SB-216763;S280744-09-4 O=C(NC1=O)371.2168 Autophagy; ### HY-15290 AIM-100 AIM 100;AIM 873305-35-2 C1(C2=C(C 371.4317 Ack1### HY-B0789 SU6656 SU-6656 330161-87-0 O=S(C1=CC2371.4533 Src### HY-10012 AZD-5438 AZD 5438;A 602306-29-6 O=S(C1=CC=371.4566 CDK### HY-50855B CX-4945 (sodSilmitasertib 1309357-15- O=C(C1=CC=371.7523 Autophagy; C### HY-12017 PF-04217903PF04217903;956905-27-4 OCCN1N=CC372.3833 c-Met/HGFR### HY-N0893 Tetrahydroc HZIV 81-2 36062-04-1 O=C(CC(CCC372.4117 Autophagy; ### HY-15166 SB1317 TG02;SB 131937270-47-8 CN1CC2=CC(372.4629 CDK; FLT3; J### HY-18657 TEPP-46 ML-265 1221186-53- O=C1C(N(C) 372.4645 PDK-1### HY-16962A CC-115 (hydrochloride) 1300118-55- [H]Cl.O=C1 372.8122 DNA-PK; mT### HY-101053 Src Inhibitor Src Kinase In179248-59-0 COC1=CC2=373.40456 Src### HY-10228 Motesanib AMG 706; AM453562-69-1 O=C(C1=CC 373.4509 c-Kit; VEGFR### HY-11007 GNF-2 GNF 2;GNF2 778270-11-4 O=C(C1=CC=374.3166 Bcr-Abl### HY-50751 Linifanib ABT-869;AL- 796967-16-3 O=C(NC1=CC375.3989 Autophagy; ### HY-13895 WHI-P154 WHI-P 154 211555-04-3 OC1=CC=C(N376.2047 JAK; VEGFR### HY-50683 JNJ-3887760 JNJ38877605 943540-75-8 FC(F)(C1=N 377.3502 c-Met/HGFR### HY-12292 IM-12 IM 12;IM12 1129669-05- O=C(C(NCCC377.4115 GSK-3### HY-15466 CH5132799 CH 5132799;1007207-67- NC1=NC=C(C377.4214 PI3K### HY-10256 SB 203580 RWJ 64809;S152121-47-6 O=S(C1=CC=377.4346 Akt; Autopha### HY-10595 Ro 28-1675 Ro 028-1675 300353-13-3 O=C(NC1=NC378.5089 Glucokinase### HY-18958 CCT245737 CCT 245737;1489389-18- FC(F)(F)C( 379.3398 Checkpoint K### HY-10366 BI-78D3 BI 78D3 883065-90-5 O=C1N(C2=C379.37106 JNK### HY-15604 AZD1208 AZD 1208;AZ1204144-28- O=C(NC/1=O379.4753 Pim### HY-13864 PF-4989216 1276553-09- N#CC1=C(N2380.3988 PI3K### HY-101244 ZINC008815 ZINC-008815557782-81-7 O=C(NC1=NC380.4601 ROCK### HY-10008 SNS-032 BMS-387032;345627-80-7 CC(C)(C1=C 380.528 CDK### HY-10325 CL-387785 EKI-785;WAY194423-06-8 O=C(NC1=CC381.226 EGFR### HY-19712 LJH685 LJH 685;LJH- 1627710-50- OC1=C(F)C=381.4185 Ribosomal S6### HY-50514 AT9283 AT-9283;AT 896466-04-9 O=C(NC1CC 381.4316 Aurora Kinas

### HY-13838 PLX647 PLX-647 873786-09-5 FC(C1=CC=C382.3817 c-Fms; c-Kit### HY-15192 GSK 650394 GSK650394; 890842-28-1 O=C(O)C(C=382.4544 SGK### HY-100213 EAI045 EAI 045;EAI- 1942114-09- O=C(C(C1=C383.3961 EGFR### HY-10402 Losmapimod GSK-AHAB;G 585543-15-3 CC1=C(C2=N383.4591 Autophagy; ### HY-10172 IMD-0354 978-62-1 O=C(NC1=CC(383.6729 IKK### HY-12048 Chelerythrine Chloride 3895-92-9 C[N+]1=CC2383.8249 Autophagy; ### HY-13264 WP1130 Degrasyn;WP856243-80-6 BrC1=CC=CC384.2697 Autophagy; B### HY-10115A PI-103 (HydroPI 103 hydro 371935-79-4 OC1=CC(C2=384.8163 mTOR; PI3K### HY-15779A K145 (hydrocSphK2 inhibi 1449240-68- O=C(N(CCN) 384.9207 SPHK### HY-12948 AMG319 AMG-319;AM1608125-21- C[C@H](NC 385.397 PI3K### HY-16715 Acumapimod 836683-15-9 O=C(NC1CC1385.4185 p38 MAPK### HY-15615 TIC10 isomerONC201 isom41276-02-2 O=C(C(C1)= 386.4894 Akt; ERK; TN### HY-15615A TIC10 TIC-10;ONC- 1616632-77- O=C1N(CC2 386.4894 Akt; ERK; TN### HY-100627 APS-2-79 APS 2-79 2002381-25- CC1=CC(OC 387.4312 ERK### HY-10322 BIBX 1382 Falnidamol; 196612-93-8 ClC1=CC(NC 387.8418 EGFR### HY-18685 CPDA 1415834-63- O=C(NC1=NC388.7951 Src### HY-18299A Purvalanol A NG-60 212844-53-6 CC([C@@H]( 388.8944 Autophagy; ### HY-19352 T56-LIMKi T5601640 924473-59-6 O=C(C1=CC(389.328 LIM Kinase (### HY-13343 ZM 336372 ZM336372;Z 208260-29-1 O=C(NC1=CC389.447 Raf### HY-12046 PIK-93 PIK 93;PIK93 593960-11-3 CC(NC1=NC(389.8775 PI3K; PI4K### HY-15773 PF-4708671 PF 4708671; 1255517-76- FC(C1=CC=C390.4055 Ribosomal S6### HY-10510 BI-D1870 BI-D 1870 501437-28-1 OC1=C(F)C=391.415 Autophagy; R### HY-15424 5-IodotuberciNSC 113939; 24386-93-4 NC1=C2C(N(392.1498 Adenosine Ki### HY-14537 Latrepirdine Dimebolin di 97657-92-6 CN(C1)CCC2 392.3652 AMPK; Autop### HY-50905 Dovitinib CHIR-258;TKI405169-16-6 O=C1NC(C=C392.4294 c-Kit### HY-19912 Fruquintinib HMPL-013;HM1194506-26- O=C(C1=C(C393.3927 VEGFR### HY-50896 Erlotinib NSC 718781;183321-74-6 C#CC1=CC=393.4357 Autophagy; ### HY-14711 Reversine 656820-32-5 C1(NC2=CC=393.4854 Aurora Kinas### HY-13261 A66 A 66; A-66 1166227-08- CC(C)(C1=N 393.5268 PI3K### HY-13329 IRAK-1-4 InhibIRAK-1/4 Inhi509093-47-4 O=C(C1=CC=395.4118 IRAK### HY-12016 KU-55933 KU 55933;KU587871-26-9 O=C1C=C(OC395.4946 ATM/ATR; Au### HY-101296 PD-166866 PD 166866;P 192705-79-6 O=C(NC(C)( 396.44296 FGFR### HY-10330 Toceranib SU 11654;PH356068-94-5 O=C(NCCN1C396.4579 PDGFR; VEG### HY-13280 IRAK inhibito 4-Thiazoleca 1042672-97- COC1=CC(N 396.4628 IRAK### HY-10492 Dinaciclib SCH 727965;779353-01-4 OCC[C@H]1N396.486 CDK### HY-13454 CID 2011756CID2011756;638156-11-3 O=C(C1=CC=396.8667 PKD### HY-10110 IC-87114 IC87114;IC 371242-69-2 O=C1N(C(CN397.4326 PI3K### HY-10324 D4476 Casein Kinas 301836-43-1 O=C(N)C1=C398.414 Autophagy; C### HY-100339 GSK583 GSK-583;GSK1346547-00- FC1=CC2=C(398.4539 RIP kinase### HY-10255A Sunitinib SU 11248;SU557795-19-4 O=C(NCCN(C398.4738 Autophagy; ### HY-12768 BLZ945 BLZ-945 953769-46-5 O=C(C1=NC=398.4787 c-Fms### HY-16667 HLM006474 HLM 006474 353519-63-8 OC(C1=NC(C399.4849 ATM/ATR### HY-10456 TAK-715 TAK 715;TAK303162-79-0 O=C(C1=CC=399.508 p38 MAPK

### HY-15339 CVT-313 CVT 313;NG 199986-75-9 CC(N1C=NC2400.4747 CDK### HY-13060 406209-26-5 N#CC1=C(C=400.9018 IKK### HY-12644 Acalisib GS-9820;GS9870281-34-8 O=C1N(C2=C401.3965 PI3K### HY-10005 Flavopiridol L868275; HMR146426-40-6 O=C1C2=C(C401.8402 Autophagy; ### HY-N0674A Dehydrocoryd13-Methylpal10605-03-5 CC1=C(C=CC401.88326 p38 MAPK### HY-10401 VX-702 VX702;VX 70745833-23-2 O=C(N)C1=C404.3178 p38 MAPK### HY-13287 SGI-1776 SGI 1776;SG 1025065-69- CN1CCC(CC1405.4168 Autophagy; ### HY-12215 PF-06463922Lorlatinib;P 1454846-35- CN1C(C#N)=406.413 ALK### HY-12513 LY3023414 LY-3023414; 1386874-06- O=C(N1C[[email protected] DNA-PK; mTO### HY-12497 ANA-12 219766-25-3 O=C(C1=CC 407.4854 Trk Receptor### HY-13300 SR-3677 SR3677;SR 31072959-67- CN(C)CCOC1408.4503 Autophagy; ### HY-10344 AZD 6482 AZD6482;AZD1173900-33- O=C1N2C(C(408.4503 Autophagy; P### HY-12063 PHT-427 PHT 427;PHT1191951-57- CCCCCCCCCC409.609 Akt### HY-10527 Telatinib Bay 57-9352 332012-40-5 O=C(C1=NC=409.8257 c-Kit; PDGFR### HY-15490 PF-670462 PF 670462;P 950912-80-8 NC1=NC=CC(410.3159 Casein Kinas### HY-70063 NVP-BKM120BKM-120;BK 944396-07-0 FC(F)(C1=C 410.3936 PI3K### HY-12059A AT7867 (dihyAT-7867 dihy1431697-86- ClC1=CC=C(410.7678 Akt### HY-12868 PQR309 Bimiralisib; 1225037-39- NC1=NC=C(C411.3816 PI3K### HY-15968 GS-9973 Entospletini 1229208-44- C12=NC=CN411.4591 Syk### HY-15467A ZM323881 (hyZM-323881 hy193000-39-4 CC1=C(O)C=411.8566 VEGFR### HY-100037 NT157 NT-157;NT 151384426-12- S=C(NCC1=C412.2551 Insulin Recep### HY-13404 INCB28060 Capmatinib; 1029712-80- O=C(NC)C1 412.4191 c-Met/HGFR### HY-12055 BIX02188 BIX 02188;B 334949-59-6 O=C(N)C1=C412.4837 MEK### HY-15557 AZ20 AZ-20;AZ 20 1233339-22- O=S(C1(C2=412.5052 ATM/ATR### HY-19323 AZD6738 AZD-6738 1352226-88- O=[S@@](C1412.5085 ATM/ATR### HY-11006 KU-57788 KU 57788; N 503468-95-9 O=C1C=C(N 413.4883 CRISPR/Cas9;### HY-51424 PLX-4720 PLX4720;PLX918505-84-7 O=S(NC1=CC413.8262 Raf### HY-10256A SB 203580 (hRWJ 64809 hy869185-85-3 O=S(C1=CC=413.8956 Akt; Autopha### HY-15494 AXL1717 Picropodophy477-47-4 O=C1OC[C@]414.4053 IGF-1R### HY-101667 LTURM34 LTURM 34;L 1879887-96- O=C1C2=CC414.47632 DNA-PK### HY-12763 GNE-317 1394076-92- NC1=NC=C(C414.4814 mTOR; PI3K### HY-100498 GSK2256098GSK-22560981224887-10- O=C(NOC)C1414.8886 FAK### HY-18199 SKLB610 SKLB 610;SK 1125780-41- O=C(C1=NC=415.3652 FGFR; PDGFR### HY-13026 CAL-101 CAL101;GS-11870281-82-6 O=C1N(C2=C415.423 Autophagy; P### HY-N2149 Tomatidine 77-59-8 [H][C@]1(O[ 415.6517 Akt; ERK; NF### HY-13256 OSI-420 Desmethyl Er183320-51-6 OCCOC1=CC415.8701 EGFR### HY-13820 GSK2656157GSK 26561571337532-29- CC1=CC=CC(416.4508 PERK### HY-12060 KRN-633 KRN 633;KR 286370-15-8 ClC1=CC(OC 416.8582 VEGFR### HY-17044A Duvelisib (R IPI-145 R en 1261590-48- ClC1=C(C2= 416.863 PI3K### HY-17044 Duvelisib IPI-145;IPI 1201438-56- O=C1N(C2=C416.863 PI3K### HY-50847 ZSTK474 ZSTK-474;ZS475110-96-4 FC(C1=NC2=417.4125 Autophagy; P### HY-12050 CP-673451 CP 673451;C343787-29-1 NC1CCN(C2=417.5035 PDGFR### HY-16749 Pexidartinib PLX-3397 1029044-16- FC(C1=CC=C417.8148 c-Fms; c-Kit

ACHP (Hydrochloride)

### HY-15738 GNF-5 GNF 5;GNF5 778277-15-9 FC(F)(F)OC 418.3692 Bcr-Abl### HY-101126 TP-3654 TP3654;TP 3 1361951-15- OC(C)(C)[C 418.4553096Pim### HY-50943 AT7519 (HydrAT 7519 Hydr902135-91-5 O=C(C(C(Cl 418.7054 CDK### HY-12018 Vatalanib PTK787;PTK/ 212141-51-0 ClC1=CC=C(419.7348 VEGFR### HY-13263 CHIR-124 CHIR124;CHI405168-58-3 ClC1=CC2=C419.9067 Checkpoint K### HY-10191 Linsitinib OSI 906;OSI- 867160-71-2 O[C@@]1(C) 421.4937 IGF-1R; Insul### HY-12599 URMC-099 1229582-33- CN(CC1)CCN 421.5368 Autophagy; M### HY-15868 HS-173 HS173;HS 171276110-06- O=C(C1=CN=422.457 PI3K### HY-18012 AVL-292 Spebrutinib; 1202757-89- COCCOC1=CC423.4402 Btk### HY-100221 AM-2394 AM2394;AM 1442684-77- O=C(NC)NC1423.465 Glucokinase### HY-100394 NVP-BAW288BAW2881;BA861875-60-7 O=C(C1=C2C424.3753 VEGFR### HY-12045 HMN-214 IVX-214;HMN173529-46-9 CC(N(C1=C( 424.4696 Polo-like Kin### HY-12558 LY3009120 DP-4978;LY- 1454682-72- O=C(NC1=CC424.5144 Autophagy; R### HY-13022 CC-401 (hydrCC 401 hydro1438391-30- C1(C2=CC=C424.9265 JNK### HY-15177 PF-04691502PF 046915021013101-36- OCCO[C@@H]425.4809 mTOR; PI3K### HY-10249 GSK-690693 GSK 690693 937174-76-0 CC(O)(C)C# 425.4842 Akt; Autopha### HY-12795 Vps34-IN-1 1383716-33- CC(C)(O)CN 425.9146 PI3K### HY-12031 U0126 U0126-EtOH;1173097-76- NC1=CC=CC=426.5583 Autophagy; ### HY-10981 Lenvatinib E7080;E-708 417716-92-8 O=C(N)C1=C426.853 VEGFR### HY-15727 Afuresertib GSK 21101831047644-62- O=C(C1=CC(427.3232 Akt; PKA### HY-15164 Icotinib (Hyd BPI-2009H 1204313-51- C#CC1=CC(N427.8808 EGFR### HY-12866 LOXO-101 ARRY470;ARR1223403-58- O=C(N1C[[email protected] Trk Receptor### HY-13698 Nandrolone 19-Nortestos 360-70-3 C[C@@]12[C428.6472 Akt; mTOR### HY-15431 AZD5363 AZD-5363;AZ1143532-39- O=C(C1(N)C 428.9152 Akt; Autopha### HY-15965 GSK2141795Uprosertib; 1047634-65- O=C(C1=CC(429.248 Akt### HY-18304 BMS-3 BMS3;BMS 3 1338247-30- O=C(C1CC1)429.2712 LIM Kinase (### HY-12624 ON123300 ON-123300;O1357470-29- N#CC1=CC2=429.5175 CDK### HY-12277 AZ191 AZ-191 1594092-37- CN1C2=CN=C429.5175 DYRK### HY-12008 Erlotinib (Hy CP-358774;O183319-69-9 COCCOC1=CC429.8967 Autophagy; ### HY-15323 PRT062607 (HP505-15 Hydr1370261-97- NC(C1=CN=C429.9066 Syk### HY-12042 AS703026 Pimasertib; 1236699-92- FC1=C(C=CC431.2008 MEK### HY-18305 BMS-5 LIMKI-3;BMS51338247-35- CC(C)C(NC1 431.2871 LIM Kinase (### HY-13819 MK-8745 MK8745;MK 885325-71-3 O=C(C1=CC=431.9142 Aurora Kinas### HY-11000 GSK429286AGSK 429286A864082-47-3 O=C(C(C(C1 432.3709 ROCK### HY-12653 LDC4297 LDC 4297;LD1453834-21- CC(C)C1=C 432.5214 CDK### HY-18299 Purvalanol B NG 95;NG95;212844-54-7 O=C(O)C1=C432.9039 CDK### HY-15816 VRT752271 Ulixertinib; 869886-67-9 O=C(C1=CC(433.331 ERK### HY-15245 GSK2636771GSK 26367711372540-25- CC1=NC2=C(433.4236 PI3K### HY-10223 CUDC-101 CUDC101;CU1012054-59- C#CC1=CC=C434.4876 EGFR; HDAC### HY-15777 LEE011 Ribociclib;L 1211441-98- O=C(N(C)C) 434.5373 CDK### HY-14394 TBB NSC 231634;T17374-26-4 BrC1=C2C(NN434.7083 Casein Kinas### HY-10328 VX-745 VX 745;VX74209410-46-8 O=C1N=CN(C436.2621 p38 MAPK### HY-14720 LY2603618 IC-83;LY 26 911222-45-2 BrC(C=C1NC436.303 Autophagy; C

### HY-10208 Pazopanib GW 786034; 444731-52-6 O=S(C1=CC(437.518 Autophagy; c### HY-15749 XL228 XL-228;XL 2 898280-07-4 CN1CCN(C2=437.5412 Aurora Kinase### HY-10006 Flavopiridol HL 275;NSC 131740-09-5 O=C1C2=C(C438.3011 Autophagy; ### HY-10343 Sotrastaurin AEB071;AEB 425637-18-9 O=C(C(C1=C438.4812 PKC### HY-12965 S49076 S 49076;S-4 1265965-22- O=C(N1CC2=438.4995 FGFR; TAM R### HY-10997 PCI-32765 Ibrutinib;PC 936563-96-1 C=CC(N1C[C440.4971 Btk### HY-12056 BIX02189 BIX 02189;B 1265916-41- O=C(N(C)C) 440.5368 MEK### HY-10045 AEE788 AEE-788;AEE497839-62-0 C[C@H](C1=440.5832 EGFR### HY-15202 MEK162 Binimetinib 606143-89-9 BrC1=CC=C(441.2268 Autophagy; ### HY-10336 Brivanib (ala BMS-582664 649735-63-7 O=C(O[C@@H441.4555 Autophagy; ### HY-15244 BYL-719 Alpelisib;BY 1217486-61- CC(N=C(S1) 441.4705 PI3K### HY-10501 SU14813 SU-14813;SU627908-92-3 O=C(C1=C(C442.4833 PDGFR; VEG### HY-13689 Go 6983 Go6983;Go-6133053-19-7 O=C(C(C1=C442.5096 PKC### HY-13561 AZM475271 AZM-475271 476159-98-5 CN1CCC(COC442.9385 Src### HY-10204 OSI-930 OSI 930;OSI 728033-96-3 O=C(C1=C(N443.4416 c-Fms; c-Kit### HY-13223 Crenolanib CP-868596;C670220-88-9 NC1CCN(C2=443.5408 Autophagy; ### HY-13304 LY2874455 LY 2874455; 1254473-64- ClC1=CN=CC444.3139 FGFR### HY-15999 Cerdulatinib PRT062070;P1198300-79- O=S(N(CC1) 445.5385 JAK; Syk### HY-100398 PF-04979064PF 049790641220699-06- O=C(N1C2CC446.5016 PI3K### HY-18708 Erdafitinib JNJ42756493;1346242-81- CN1N=CC(C2446.5447 FGFR### HY-15180 NVP-BKM120 BKM-120 hydr1312445-63- NC(N=C1)=C446.8545 PI3K### HY-50895 Gefitinib ZD 1839;ZD-184475-35-2 ClC1=C(C=C446.9024 Autophagy; ### HY-18179 AZD2932 AZD-2932;AZ883986-34-3 O=C(NC1=CN447.4864 PDGFR; VEG### HY-10206 Amuvatinib MP-470;MP 4850879-09-3 S=C(N1CCN 447.5096 c-Kit; FLT3;### HY-N0418 Quercitrin Quercetin 3- 522-12-3 OC1=CC(O)=448.3769 Autophagy; R### HY-11105 PI3K inhibitor X 956958-53-5 O=S(C1=CC 448.5208 PI3K### HY-15609 AZD-3463 AZD3463;AZD 1356962-20- ClC(C=NC(N 448.9479 ALK; Autopha### HY-50878 Crizotinib PF02341066;877399-52-5 ClC1=C(F)C 450.3367 ALK; Autopha### HY-10205 Cediranib AZD2171;AZD288383-20-0 FC1=C(OC2=450.5053 Autophagy; ### HY-12495 ISRIB (trans-isomer) 1597403-47- O=C(N[C@@H451.343 PERK### HY-18072 GSK2606414GSK 26064141337531-36- NC1=C2C(N(451.4437 PERK### HY-11004 AZ 628 AZ-628;AZ62878739-06-1 O=C1N(C)C=451.5197 Raf### HY-101493 SUN11602 SUN-11602;S704869-38-5 O=C(N)C1=C451.60428 FGFR### HY-15307 SLx-2119 SLx 2119;SLx911417-87-3 O=C(NC(C)C 452.5078 ROCK### HY-15761 AZD2858 AZD 2858;AZ486424-20-8 O=C(C1=NC(453.5174 GSK-3### HY-10966 SB-590885 SB590885;SB405554-55-4 O/N=C1CCC2453.5356 Raf### HY-15771 ONO-4059 ONO4059;ONO1351636-18- O=C1N(C2=C454.4806 Btk### HY-10977 Tivozanib AV-951;AV95475108-18-0 O=C(NC1=CC454.8631 VEGFR### HY-12964 SGI-7079 SGI7079;SGI 1239875-86- N#CCC1=CC=455.5299 TAM Recepto### HY-15610 GDC-0623 GDC0623;GD1168091-68- FC(C=C(I)C 456.2102 MEK### HY-10247 BRAF inhibito2-Propanesulf918505-61-0 CC(C)S(=O) 456.4651 Raf### HY-18951 ONO-4059 (aONO 4059 an1351635-67- O=C1N([[email protected] Btk### HY-12330 AZD8186 AZD-8186 1627494-13- O=C(C1=CC(457.4698 PI3K

### HY-14761 AS 602801 Bentamapimo848344-36-5 N#CC(C1=N 457.5474 JNK### HY-50706 Selumetinib AZD6244;Arr606143-52-6 O=C(C1=C(C457.6814 MEK### HY-15186 GDC-0068 Ipatasertib 1001264-89- ClC1=CC=C(457.9962 Akt### HY-18750 AZD3759 AZD-3759 1626387-80- ClC1=CC=CC459.9011 EGFR### HY-15241 NVP-LCQ195 LCQ-195;AT- 902156-99-4 CS(=O)(N1C 460.3349 CDK### HY-13898 GDC-0032 Taselisib;R 1282512-48- CC(C)N1C(C 460.5315 PI3K### HY-10424 PHA-848125 Milciclib;PH 802539-81-7 O=C(NC)C1=460.5746 Autophagy; ### HY-12058 AZD8330 ARRY-424704869357-68-6 IC1=CC(F)= 461.2267 MEK### HY-100573 Necrosulfonamide 1360614-48- O=C(NC1=CC461.4716 Mixed Lineag### HY-10200 BMS-754807 BMS 754807 1001350-96- C[C@]1(CCC 461.4948 IGF-1R; Insul### HY-100016 AZD0156 AZD-0156;AZ1821428-35- O=C(N1C2CC461.556 ATM/ATR### HY-50909 Perifosine KRX-0401;NS157716-52-4 [O-]P(OC1C 461.6584 Akt; Autopha### HY-13252 MK-5108 MK 5108;VX-1010085-13- FC(C(Cl)=C 461.9368 Aurora Kinas### HY-18095 CX-6258 CX6258;CX 61202916-90- O=C1NC2=CC461.9401 Pim### HY-14981 GSK2334470GSK 23344701227911-45- O=C([C@@H]462.5905 PDK-1### HY-15969 Sal003 Sal-003 1164470-53- O=C(NC(NC(N463.2082 PERK### HY-14985 BAY 61-3606 BAY61-3606 d648903-57-5 O=C(N)C1=C463.3172 Syk### HY-18696 AMG-337 AMG337;AMG1173699-31- O=C1C2=C(N463.4643 c-Met/HGFR### HY-13902 VE-822 VE822;VE 821232416-25- NC1=NC=C(C463.552 ATM/ATR### HY-13330 AZD4547 AZD 4547;AZ1035270-39- C[C@H](C1) 463.5719 FGFR### HY-15798 UNC2881 UNC 2881;UN1493764-08- CCCCNC1=NC463.5752 TAM Recepto### HY-15727A Afuresertib ( GSK 2110183 1047645-82- O=C(C1=CC(463.7841 Akt; PKA### HY-18955 BI-847325 BI847325;BI 1207293-36- O=C(NCC)C#464.5582 Aurora Kinas### HY-10161 Tozasertib MK-0457;VX-639089-54-6 CC1=CC(NC2464.5864 Aurora Kinas### HY-13018 MRT67307 MRT 67307; 1190378-57- O=C(NCCCNC464.603 Autophagy; I### HY-10201 Sorafenib Bay 43-9006 284461-73-0 O=C(NC(C=C464.825 Autophagy; c### HY-10182 CHIR-99021 CT99021;CHI252917-06-9 N#CC1=CC=C465.3379 Autophagy; ### HY-17600 AcalabrutinibACP-196;ACP1420477-60- O=C(NC1=NC465.5065 Btk### HY-16265 JI-101 JI 101;JI101 900573-88-8 O=C(NC1=C 466.3305 Ephrin Recep### HY-13228 YM-201636 YM 201636; 371942-69-7 O=C(NC1=C 467.4793 Autophagy; P### HY-32718 Pelitinib EKB-569;WAY257933-82-7 N#CC1=C(C2467.9231 EGFR### HY-13501 Mubritinib TAK-165 366017-09-6 FC(C1=CC=C468.4709 EGFR### HY-12017A PF-04217903PF04217903 956906-93-7 OCCN1N=CC(468.489 c-Met/HGFR### HY-12334 HTH-01-015 HTH 01 015 1613724-42- O=C1C(C=C2468.5535 AMPK### HY-10497 BMS-794833 1174046-72- ClC1=C(OC2 468.84 c-Met/HGFR;### HY-13203 NVP-TAE 226TAE226 761437-28-9 O=C(C1=C(C468.936 FAK; Pyk2### HY-12038 Ki8751 Ki 8751;Ki-8 228559-41-9 COC1=CC2=C469.4126 VEGFR### HY-14674 CP-724714 CP 724714;C383432-38-0 O=C(COC)NC469.535 EGFR### HY-12869 AZD-8835 1620576-64- O=C(N1CCC(469.54 PI3K### HY-13272 Dacomitinib PF-002998041110813-31- O=C(/C=C/C 469.939 EGFR### HY-13034 LY2784544 LY 2784544;L1229236-86- CC1=NNC(NC469.9423 FGFR; FLT3; ### HY-11108 R406 (free b R-406;R406 841290-80-0 COC1=CC(NC470.4536 Syk### HY-15521 ETP-46464 ETP 46464;E 1345675-02- O=C1N(C2=C470.5213 ATM/ATR; m

### HY-100006A MRT68921 (hyMRT 68921 hydrochloride [H]Cl.O=C( 471.038 ULK### HY-11005 BX-912 BX912;BX 91702674-56-4 BrC1=C(NCC471.3536 PDK-1### HY-18652 Ro 5126766 Ro5126766;R946128-88-7 O=S(NC)(NC 471.4615 MEK; Raf### HY-13418 DorsomorphinBML-275 dihy1219168-18- [H]Cl.[H]C 472.4101 AMPK; Autop### HY-12037 Rigosertib ( ON-01910 so592542-60-4 COC1=CC=C(473.4719 Polo-like Kin### HY-13050 Sapitinib AZD-8931 848942-61-0 O=C(CN1CCC473.9277 EGFR### HY-12009 Pazopanib (HGW786034;G635702-64-6 CC1=CC=C(C473.979 Autophagy; c### HY-14574 PF-03814735PF 03814735942487-16-3 O=C(CNC(C) 474.4788 Aurora Kinas### HY-14443 XMD8-92 XMD 8-92 1234480-50- CN(C1=O)C2474.5548 ERK### HY-10179 Danusertib PHA-739358;827318-97-8 O=C(N1CC2=474.5548 Aurora Kinas### HY-10260 Vandetanib ZD6474;ZD-6443913-73-3 FC1=CC(Br) 475.354 Autophagy; ### HY-12344 UNC2025 UNC 2025;UN1429881-91- CN1CCN(CC2476.6568 FLT3### HY-15535 DMAT Casein kinase749234-11-5 CN(C)C1=NC2476.788 Casein Kinas### HY-11003 GW843682X GW 843682X660868-91-7 O=C(C1=C(O477.4562 Polo-like Kin### HY-50295 CI-1040 CI1040;CI 1 212631-79-3 O=C(C1=CC=478.6595 MEK### HY-16082 AZD7545 AZD 7545;AZ252017-04-2 O=C(N(C)C)C478.8698 PDHK### HY-14177 B-Raf inhibit 1,5-Isoquinol1093100-40- CC1=CC=C2478.9357 Raf### HY-14715B CCT241533 (hCCT-241533 h1431697-96- [H]Cl.COC1 478.9442 Checkpoint K### HY-15158 SBE13 (HydroSBE-13 Hydro1052532-15- COC1=CC=C(479.3961 Autophagy; Po### HY-15486 Salubrinal 405060-95-9 O=C(NC(NC( 479.8099 Autophagy; ### HY-100519 NVS-PAK1-1 1783816-74- FC1=CC2=C(479.9257 PKA### HY-10262 BMS-536924 BMS536924; 468740-43-4 O=C1C(C2=N479.9586 IGF-1R; Insul### HY-10358 MK 2206 (dihMK-2206 dihy1032350-13- O=C1N2C(C3480.389 Akt; Autopha### HY-16069 Irbinitinib ARRY-380;ON937263-43-9 CC1=CC(NC 480.5211 EGFR### HY-10254 PD0325901 PD 0325901;391210-10-9 O=C(C1=CC=482.1931 Autophagy; ### HY-10207 Dovitinib (lacCHIR-258 lact692737-80-7 O=C(N1)C(C 482.5073832FGFR### HY-13011 CH5424802 Alectinib;A 1256580-46- N#CC1=CC2=482.6165 ALK### HY-10331 Regorafenib BAY 73-4506755037-03-7 O=C(NC1=CC482.8154 Autophagy; ### HY-13687 IKK 16 IKK16;IKK-16873225-46-8 O=C(C1=CC=483.6277 IKK### HY-50767A Palbociclib ( PD-0332991 h827022-32-2 O=C1C(C(C) 483.9937 CDK### HY-B0788 LY2409881 LY-2409881 946518-61-2 O=C(C1=C(C485.0446 IKK### HY-B0793 AZ-5104 1421373-98- C=CC(NC1=C485.5807 EGFR### HY-10261 Afatinib BIBW-2992;B850140-72-6 O=C(NC1=C(485.9384032Autophagy; ### HY-13076 CHIR-98014 CHIR98014;C252935-94-7 ClC1=CC(Cl 486.3141 GSK-3### HY-19730 Olmutinib 1353550-13- C=CC(NC1=C486.5887 EGFR### HY-50878A Crizotinib (h PF-02341066 1415560-69- ClC1=C(F)C 486.7976 ALK; Autopha### HY-10181 Dasatinib BMS-354825 302962-49-8 O=C(C1=CN=488.0056 Autophagy; B### HY-B0764A Bucladesine (Dibutyryl-cA 938448-87-4 O=C(CCC)O[ 488.42 PKA### HY-13281 PIK-75 PIK-75 Hydro372196-77-5 BrC(C=C1)=C488.7434 DNA-PK### HY-15240 DCC-2618 DCC 2618;D 1225278-16- O=C(C1(CC1489.4734 c-Kit; c-Met### HY-10303 PIK-294 900185-02-6 O=C1N(C2=C489.5279 PI3K### HY-12057 VemurafenibPLX-4032;RG918504-65-1 FC1=CC=C(C489.9221 Autophagy; R### HY-13007 PF-3758309 PF 3758309; 898044-15-0 CC1=NC2=C(490.6237 PAK

### HY-15730 Poziotinib HM781-36B; 1092364-38- C=CC(N1CCC491.3423 EGFR### HY-B0764 Bucladesine Dibutyryl-cA 16980-89-5 O=C(CCC)O[ 491.3675 PKA### HY-10461 PF-573228 PF573228;PF869288-64-2 O=C1NC2=C(491.4861 FAK### HY-14721 EMD-121406Tepotinib;E 1100598-32- N#CC1=CC=C492.5716 Autophagy; ### HY-13342 Apatinib YN 968D1;YN1218779-75- O=C(C1=CC=493.578 Autophagy; ### HY-15463 Imatinib STI571;STI 5 152459-95-5 CN(CC1)CCN 493.6028 Autophagy; B### HY-10330A Toceranib (p SU 11654;PH874819-74-6 O=C(NCCN1C494.4531 PDGFR; VEG### HY-12026 WZ4002 WZ 4002;WZ1213269-23- COC1=C(C=C494.9733 EGFR### HY-50940A AT7519 (trifl AT 7519 trifl 1431697-85- O=C(NC1=CN496.2678 CDK### HY-15802 WZ4003 WZ 4003;WZ1214265-58- O=C(NC1=CC496.9892 AMPK### HY-12049 CCT129202 CCT-129202;942947-93-5 CN(C1=CC=C497.0156 Aurora Kinas### HY-13246 GDC-0980 GNE 390;GDC1032754-93- C[C@@H](C( 498.6011 mTOR; PI3K### HY-10209 Masitinib AB1010;AB-1790299-79-5 O=C(NC1=CC498.6424 c-Kit; PDGFR### HY-13943 CNX-774 CNX774;CNX1202759-32- O=C(NC)C1=499.4964 Btk### HY-13231 CDK9-IN-1 1415559-43- CC1=C(NS(C 499.541 CDK; HIV### HY-15772 AZD-9291 Osimertinib; 1421373-65- C=CC(NC1=C499.6073 EGFR### HY-14178 VX-11e VX 11e 896720-20-0 FC1=CC(Cl) 500.3523 ERK### HY-10993 MK-1775 AZD-1775;AZ955365-80-7 O=C1N(N(C2500.5954 Wee1### HY-10331A Regorafenib BAY 73-45061019206-88- O=C(NC1=CC500.8307 Autophagy; ### HY-13917 PND-1186 SR-2516;PND1061353-68- O=C(NC)C1=501.5009 FAK### HY-13016 CabozantinibXL184;BMS-9849217-68-1 O=C(C1(CC1501.5057 c-Kit; c-Met### HY-10178 PHA-680632 PHA680632; 398493-79-3 O=C(N1CC2=501.6232 Aurora Kinas### HY-13258 NVP-BHG712NVP-BHG 712940310-85-0 CC1=CC=C(C503.4785 Ephrin Recep### HY-13253 AMG 900 AMG-900;AM945595-80-2 CC1=CSC(C2503.5776 Aurora Kinas### HY-13449 TAK-733 TAK733;TAK 1035555-63- O=C1C(C(NC504.2267 MEK### HY-12201 TAK-901 TAK901;TAK 934541-31-8 O=C(NC1CCN504.6437 Aurora Kinas### HY-10297 GSK2126458Omipalisib; 1086062-66- COC1=NC=C(505.496 mTOR; PI3K### HY-15246 MLN 2480 BIIB-024;ML 1096708-71- NC1=NC=NC(506.2891 Raf### HY-12235 PI-3065 PI3065;PI 30 955977-50-1 FC(C=CC1=C506.638 PI3K### HY-10126 AZD1152-HQBarasertib; 722544-51-6 O=C(CC1=NN507.5599 Aurora Kinas### HY-13319 JNK-IN-8 (E)-3-(4-(di 1410880-22- CC1=CC(NC(507.5863 JNK### HY-70044 GSK-107091 GSK1070916;942918-07-2 O=C(NC1=CC507.6293 Aurora Kinas### HY-12823 BLU9931 BLU-9931 1538604-68- C=CC(NC1=C509.3839 FGFR### HY-10410 TG101209 TG 101209;T936091-14-4 O=S(C1=CC=509.6668 Autophagy; E### HY-12289 Defactinib VS-6063;VS61073154-85- O=C(NC)C1=510.4927 FAK### HY-16294 LY2090314 LY 2090314; 603288-22-8 O=C(C(C1=C512.5349 GSK-3### HY-12076 BMS 777607 BMS777607; 1025720-94- O=C(NC1=CC512.8926 c-Met/HGFR;### HY-10406 SCIO-469 Talmapimod;309913-83-5 O=C(N(C)C) 513.0035 p38 MAPK### HY-12344A UNC2025 (hydUNC-2025 hydrochloride CN1CCN(CC2513.1177 FLT3### HY-15542B FRAX486 FRAX-486 1232030-35- FC1=CC(NC2513.3941 PAK### HY-12846 CCT196969 CCT-196969;1163719-56- O=C1NC2=NC513.5229 Raf### HY-10128 ZM-447439 ZM447439;Z 331771-20-1 O=C(NC1=C 513.5875 Aurora Kinas### HY-50094 GDC-0941 Pictilisib;G 957054-30-7 CS(N1CCN(C 513.6356 Autophagy; P

### HY-10342 Enzastaurin LY317615;LY170364-57-5 O=C(C(C1=C515.605 Autophagy; ### HY-12963 TP-0903 1341200-45- O=S(C1=CC=516.0587 TAM Recepto### HY-14440 PDK1 inhibito3-Pyridinecar1001409-50- O=C(C1=CC=516.4955 PDK-1### HY-12054 Hesperadin 422513-13-1 O=C1NC2=CC516.6544 Aurora Kinas### HY-15200 CEP-32496 CEP 32496;C1188910-76- O=C(NC1=NO517.4572 Raf### HY-10991 MGCD-265 anMGCD 265 an875337-44-3 O=C(CC1=CC517.5977 c-Met/HGFR;### HY-15358 ALK inhibitor Benzenesulfo761438-38-4 O=S(C1=C(N518.0315 ALK### HY-10248 RAF265 CHIR-265;RA 927880-90-8 FC(F)(C1=C 518.4139 Autophagy; ### HY-10971 Alisertib MLN 8237;M 1028486-01- O=C(C1=CC=518.9235 Aurora Kinas### HY-13011A CH5424802 (Alectinib Hy 1256589-74- [H]Cl.N#CC 519.0775 ALK### HY-13308 Regorafenib BAY73-4506 h835621-07-3 ClC1=C(C(F 519.2764 Autophagy; ### HY-15979A H-89 (dihydroProtein kinas130964-39-5 O=S(C1=CC=519.2826 Autophagy; ### HY-14660 Dabrafenib GSK-21184361195765-45- CC(C)(C)C1 519.5624 Raf### HY-10542 GW 5074 GW-5074;GW220904-83-6 O=C1NC2=C(520.942 Raf### HY-50698 BI 2536 BI-2536;BI25755038-02-9 O=C1[C@H](521.6544 Epigenetic R### HY-19696A TauroursodeoSodium tauro35807-85-3 C[C@H](CCC(521.6854 ERK### HY-10321 PD173074 PD 173074;P 219580-11-7 O=C(NC1=NC523.6702 FGFR### HY-10181A Dasatinib (hyBMS-354825 854001-07-3 O=C(C1=CN=524.4665 Autophagy; B### HY-10987 ENMD-2076 (TENMD 2076; 1291074-87- O[C@H](C(O 525.5569 Aurora Kinas### HY-12003 SNS-314 SNS-314 Mes1146618-41- O=C(NC1=CC527.04 Aurora Kinas### HY-10340B KX2-391 (MesKX01 Mesyla 1080645-95- O=C(NCC1=C527.6324 Microtubule/T### HY-10320 DoramapimoBIRB 796;BI 285983-48-4 O=C(NC1=CC527.6572 p38 MAPK; R### HY-100716 IPI549 IPI-549;IPI 5 1693758-51- O=C(C1=C2N528.564 PI3K### HY-13464 ALK-IN-1 1197958-12- CP(C)(C1=C 529.0139 ALK### HY-10159 Nilotinib AMN-107;Tas641571-10-0 O=C(NC1=CC529.5158 Autophagy; B### HY-15002 AST 487 NVP-AST 487630124-46-8 O=C(NC1=CC529.5573 Bcr-Abl; c-Ki### HY-12072 Lck Inhibitor 847950-09-8 O=C1N(C2=C530.6229 Src### HY-15186A GDC-0068 (diIpatasertib 1396257-94- ClC1=CC=C(530.918 Akt### HY-13064 Cobimetinib GDC-0973;XL934660-93-2 OC1([C@H]2 531.31 MEK### HY-15828 NMS-128693 NMS-P937;N 1034616-18- O=C(C1=NN(532.5182 Polo-like Kin### HY-15666 GZD824 GZD-824;GZ 1257628-77- O=C(NC1=CC532.5595 Bcr-Abl### HY-12047 Ponatinib AP 24534;AP 943319-70-8 CC1=C(C=C(532.5595 Autophagy; B### HY-13020 GSK1838705GSK 183870 1116235-97- FC1=C(C(NC 532.5693 ALK; IGF-1R; ### HY-12300 CFI-400945 (CFI400945 fr1338806-73- O=C([C@@]1534.6481 Polo-like Kin### HY-13491 GNF-5837 GNF5837;GN1033769-28- O=C(NC1=CC535.4922 Trk Receptor### HY-50904 BIBF 1120 Nintedanib;B656247-17-5 O=C1NC2=CC539.6248 FGFR; PDGFR### HY-16526 XL-147 SAR245408;XL934526-89-3 CC(C)(N)C( 541.0218 PI3K### HY-10234 Saracatinib AZD0530;AZD379231-04-6 ClC1=CC=C2542.0265 Autophagy; S### HY-50877 GSK461364 GSK 461364;929095-18-1 O=C(C(SC(N 543.6038 Polo-like Kin### HY-13897 CNX-2006 CNX2006;CN1375465-09- C=CC(NC1=C545.5319 EGFR### HY-10943 GNF-7 GNF 7;GNF7 839706-07-9 O=C(NC1=CC547.5311 Bcr-Abl### HY-12061 KU-60019 KU60019;KU 925701-46-8 C[C@@H]1O[547.6651 ATM/ATR### HY-15196 TAK-285 TAK285;TAK 871026-44-7 ClC(C=C(NC 547.9566 EGFR

### HY-10579 Pluripotin SC-1;SC1;SC 839707-37-8 CN1C(NC2=N550.535 Ribosomal S6### HY-10804 CCT 137690 CCT-137690 1095382-05- CC1=CC(CN(551.4813 Aurora Kinas### HY-10355 AKT inhibitor VIII 612847-09-3 O=C1N(C2=C551.6404 Akt### HY-15514 LY2801653 LY-2801653;M1206799-15- O=C(C1=CC=552.5309 c-Met/HGFR### HY-13979 DDR1-IN-1 1449685-96- O=C(NC1=CC552.5873 Discoidin Do### HY-15777B LEE011 (succRibociclib s 1374639-75- O=C(N(C)C) 552.6254 CDK### HY-13024 DCC-2036 Rebastinib; 1020172-07- CC(C)(C)C1 553.5869 Bcr-Abl; FLT3### HY-13866 Ro 31-8220 (Ro 31-8220 m138489-18-6 NC(SCCCN1C553.6531 PKC### HY-15767 TAK-632 TAK 632;TAK1228591-30- O=C(NC1=CC554.5154 Aurora Kinas### HY-15729 CO-1686 Rociletinib; 1374640-70- C=CC(NC1=C555.5515 EGFR### HY-15520 CGK733 CGK-733;CGK905973-89-9 FC1=CC=C(N555.8364 ATM/ATR### HY-32721 Neratinib HKI-272;HKI2698387-09-6 ClC1=C(OCC 557.0427 EGFR### HY-15656 LDK378 LDK 378;LDK-1032900-25- CC(C)OC1=C558.1351 ALK; IGF-1R; ### HY-10501A SU14813 (maSU-14813 ma849643-15-8 O=C(NC[C@@558.5554 PDGFR; VEG### HY-10367A Canertinib (dCanertinib;C 289499-45-2 C=CC(NC1=C558.8603 EGFR### HY-13311 NVP-BGJ398 Infigratinib; 872511-34-7 ClC1=C(C(C 560.4755 FGFR### HY-12494 LDC1267 LDC-1267 1361030-48- FC1=CC(NC( 560.548 TAM Recepto### HY-12678 Entrectinib NMS-E628;R 1108743-60- O=C(NC1=NN560.6375 ALK; Autopha### HY-13001 Quizartinib AC-220;AC22950769-58-1 O=C(NC1=NO560.6672 Autophagy; ### HY-12062 PD318088 PD 318088;P 391210-00-7 BrC1=CC(C( 561.0891 MEK### HY-15160 TAK-960 1137868-52- O=C(NC1CCN561.5992 Polo-like Kin### HY-13904 Flumatinib 895519-90-1 O=C(NC1=CC562.5887 Bcr-Abl; c-Ki### HY-10202 Tandutinib MLN518;CT53387867-13-2 O=C(N1CCN(562.703 FLT3### HY-80013 THZ1 CDK7 inhibit 1604810-83- ClC1=CN=C(566.0527 CDK### HY-13049 Cediranib (mAZD-2171 ma857036-77-2 O=C(O)/C=C566.5775 Autophagy; ### HY-12010 BMS-599626 (AC480;BMS-5873837-23-1 O=C(OC[[email protected] EGFR### HY-12014 SU11274 SU 11274;PK658084-23-2 O=S(C1=CC2568.0869 Autophagy; ### HY-12299 WH-4-023 Dual LCK/SRC837422-57-8 O=C(OC1=C(568.666 Src### HY-10229 Motesanib (DAMG-706;Mot857876-30-3 O=C(C1=CC=569.4413 c-Kit; VEGFR### HY-15556 GSK269962AGSK 269962A850664-21-0 CCN1C2=CC 570.5991 ROCK### HY-15777C LEE011 (succRibociclib s 1374639-79- O=C(N(C)C) 570.64 CDK### HY-12279 TGR-1202 RP5264;TGR11532533-67- O=C1C(C2=C571.5492 PI3K### HY-14691 Refametinib BAY 869766;923032-37-5 O=S(C1(C[C 572.3372 MEK### HY-A0065 Palbociclib ( PD0332991 is827022-33-3 CC(C1=C(N2 573.6644 CDK### HY-10182B CHIR-99021 (CT99021 trih1782235-14- N#CC1=CC=C574.7208 Autophagy; ### HY-50868 Bafetinib INNO-406;NS859212-16-1 O=C(C1=CC=576.6154 Autophagy; B### HY-17603 Belizatinib TSR-011 1357920-84- O=C(NC1=NC577.7325 ALK; Trk Rec### HY-11999 CGI-1746 CGI1746;CGI 910232-84-7 O=C(C1=CC=579.6887 Autophagy; B### HY-15841 CEP-37440 CEP37440;CE1391712-60- O=C(NC)C1=580.1208 ALK; FAK### HY-13326 ASP3026 ASP 3026;AS 1097917-15- COC(C=C(N1580.7447 ALK### HY-50898 Lapatinib GW572016;G231277-92-2 O=S(CCNCC1581.0576 Autophagy; ### HY-10159A Nilotinib (m AMN-107;AM923288-90-8 O=C(NC1=CC583.992 Autophagy; B### HY-12857 Brigatinib AP-26113 1197953-54- CN1CCN(C2C584.0924 ALK

### HY-10127 AZD1152 Barasertib; 722543-31-9 O=C(NC1=CC587.5398 Aurora Kinas### HY-70061 Aurora A inhibBenzamide, N-1158838-45- O=C(C1=CC=588.075 Aurora Kinas### HY-50946 Imatinib (MesCGP-57148B;220127-57-1 O=S(O)(C)= 589.7084 Autophagy; B### HY-10514 BX795 BX 795;BX-7 702675-74-9 O=C(NCCCNC591.4677 PDK-1### HY-15764A A 419259 (tr A419259 trih1435934-25- NC1=C2C(N(592.0027 Src### HY-10209A Masitinib (meAB1010 mesy1048007-93- O=C(NC1=CC594.748 c-Kit; PDGFR### HY-15772A AZD-9291 (mOsimertinib 1421373-66- C=CC(NC1=C595.713 EGFR### HY-12068 PI3K-IN-1 1349796-36- COC1=CC(NC599.6569 PI3K### HY-80013A THZ1 (HydrocCDK7 inhibitor ClC1=CN=C(602.5137 CDK### HY-16297 LY2835219 ABEMACICLIB;1231930-82- CC(N1C2=CC602.699 CDK### HY-19816A Avitinib (maleate) 1557268-88- O=C(O)/C=C603.6009032EGFR### HY-12331 KRCA-0008 KRCA 0008; 1472795-20- ClC1=CN=C(609.119 Ack1; ALK### HY-10799 EG00229 EG 00229;EG1210945-69- N=C(N)NCCC611.595 VEGFR### HY-N0154 NeohesperidiNeohesperid 20702-77-6 O=C(C1=C(O612.5764 ROS### HY-13241 LY2228820 Ralimetinib 862507-23-1 FC1=CC=C(C612.737 p38 MAPK### HY-10192 NVP-TAE 684TAE684; NVP761439-42-3 O=S(C1=CC=614.2017 ALK### HY-10999 Trametinib GSK-1120212871700-17-3 CC(NC1=CC=615.3948 MEK### HY-14660A Dabrafenib ( GSK-21184361195768-06- CC(C)(C)C1 615.6681 Raf### HY-12493A LY-2584702 (tosylate salt)1082949-68- CN1C=C(C2=617.6177 Ribosomal S6### HY-12137 Volasertib BI 6727;BI-6 755038-65-4 O=C(C1=CC=618.8126 Polo-like Kin### HY-N0605 Ginsenoside 20(S)-Ginsen78214-33-2 C[C@]([C@@]622.8727 EGFR### HY-N0021 VerbascosideActeoside;Ku61276-17-3 O[C@@H]([C624.5872 PKC### HY-12067 R406 R 406;R-406 841290-81-1 COC1=CC(NC628.6287 Syk### HY-16961 Sitravatinib MGCD516;MG1123837-84- O=C(C1(C(N 629.6763 c-Kit### HY-15656A LDK378 (dihyLDK 378 dihy1380575-43- CC(C)OC1=C631.057 ALK; IGF-1R; ### HY-18683 Centrinone-BCentrinone B1798871-31- FC(C([N+]( 631.674 Polo-like Kin### HY-10338 Foretinib XL880;GSK13849217-64-7 O=C(NC1=CC632.6537 c-Met/HGFR;### HY-18682 Centrinone 1798871-30- FC(C([N+]( 633.6468 Polo-like Kin### HY-13068 E-7050 E 7050;E705 928037-13-2 O=C(NC1=CC633.6882 c-Met/HGFR;### HY-18602 FIIN-2 FIIN2;FIIN 2 1633044-56- C=CC(NC1=C634.7274 FGFR### HY-18030A CEP-28122 (mesylate salt) O=C([C@H]1635.1746 ALK### HY-12044 CabozantinibXL184;XL-1841140909-48- O=C([C@H]( 635.5931 VEGFR### HY-15729A CO-1686 (hy Rociletinib 1446700-26- C=CC(NC1=C636.4634 EGFR### HY-10201A Sorafenib (ToBay 43-9006 475207-59-1 O=S(C1=CC=637.0266 Autophagy; c### HY-15665 XMD17-109 XMD17 109 1435488-37- O=C1C2=C(C638.8022 ERK### HY-11107 PHA-665752 PHA 665752 477575-56-7 O=C(C1=C(N641.6078 Autophagy; ### HY-15174 BEZ235 (TosyNVP-BEZ 235 1028385-32- CN(C1=C2C3641.7382 Autophagy; ### HY-11106 BIBF 1120 (eNintedanib e 656247-18-6 O=C(C1=CC(649.7571 FGFR; PDGFR### HY-13334 NVP-BGT226 NVP-BGT 2261245537-68- COC1=CC=C(650.6045 Autophagy; P### HY-12300B CFI-400945 (CFI400945 fu1616420-30- O=C(O)/C=C650.7202 Polo-like Kin### HY-13905 Flumatinib (mesylate) 895519-91-2 O=C(NC1=CC658.6945 Bcr-Abl; c-Ki### HY-10458 PF-562271 (bPF562271 bes939791-38-5 CS(=O)(N(C 665.6639 FAK; Pyk2### HY-N0014 Icariin Ieariline 489-32-7 O[C@H]1[[email protected] Autophagy; I

### HY-10999A Trametinib ( GSK-11202121187431-43- CN1C(C(C)= 693.5283 MEK### HY-18711A c-Met inhibit 1174161-86- O=C(C1=CN(699.981 c-Met/HGFR;### HY-20180 GDC-0941 (dPictilisib d 957054-33-0 O=S(N1CCN(705.8469 Autophagy; P### HY-10261A Afatinib (dimBIBW 2992MA850140-73-7 O=C(NC1=C(718.0827 Autophagy; ### HY-13290 KN-62 KN 62;KN62 127191-97-3 O=C(N1CCN(721.8444 CaMK; P2X R### HY-13038B R788 (disodi Fostamatinib914295-16-2 COC1=CC(NC2732.51 Syk### HY-N0431 Astragaloside IV 84687-43-4 O[C@H]1[[email protected] ERK; JNK; M### HY-10524 GSK1904529GSK-190452 1089283-49- O=C(C1=CC(851.9631 IGF-1R### HY-50898A Lapatinib (di GW 572016 di388082-77-7 O=S(CCNCC1925.4608 Autophagy;

3(4H)-Pyridinecarboxamide, N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-5-(4-fluorophenyl)-4-oxo-1-[(phosphonooxy)methyl]- (Tris salt)

Pathway Formula Solubility References listReferences link list Clinical InformationAutophagy; C6H7N5 DMSO: ≥ 1.5 [1] Miller S, [1] http://w No Development ReportedMAPK/ERK PaC7H7NO3 10 mM in D [1] Kruis, W. [1] http://w LaunchedAutophagy; EC4H12ClN5 H2</su[1] Soraya H,[1] http://w LaunchedCell Cycle/ C10H13NO2 10 mM in D [1] Yin Z, e [1] http://w No Development ReportedJAK/STAT Sig C10H6N2O2 DMSO: ≥ 50 [1] Lyall RM, [1] http://w No Development ReportedMAPK/ERK PaC10H8O4 DMSO: ≥ 32 [1] Pereira [1] http://w No Development ReportedProtein Tyro C9H7NO4 10 mM in D [1] Wang WY e[1] http://w No Development ReportedProtein Tyro C10H15N5 10 mM in DMSO LaunchedApoptosis C12H11NO3 DMSO: ≥ 40 [1] Sharlow E[1] https:// No Development ReportedAutophagy; C14H8N2O DMSO: ≥ 45 [1] Bennett B[1] http://w No Development ReportedApoptosis C13H19NO2 10 mM in D [1] Ren Y, et [1] https:// No Development ReportedPI3K/Akt/mTOC10H10N2O210 mM in D [1] Collino M [1] http://w No Development ReportedNF-κB C9H8N2OS2 DMSO: ≥ 53 [1] Kishore [1] http://w No Development ReportedAutophagy; C14H12O3 10 mM in D [1] http://w Phase 4Protein Tyro C15H14N2O DMSO: 22.5 [1] Fong TA, [1] http://w Phase 2Epigenetics; C14H8O4 DMSO: ≥ 42 mg/mL LaunchedAutophagy; C13H11N3O210 mM in D [1] Lane ME, [1] http://w No Development ReportedEpigenetics; C10H16ClN5 10 mM in D [1] https:// Phase 1MAPK/ERK PaC11H9FN6 DMSO: ≥ 43 [1] http://w No Development ReportedAutophagy; PC14H12O4 DMSO: ≥ 31 [1] Kazuhiro [1] www.ncbiNo Development ReportedMAPK/ERK PaC15H9N3O DMSO: ≥ 32 [1] Igor A. S [1] www.ncb No Development ReportedCell Cycle/ C12H17N5O DMSO: ≥ 32 [1] Rigas AC [1] http://w No Development ReportedCell Cycle/ C13H15NO2SDMSO: ≥ 31 [1] Muraki M,[1] http://w No Development ReportedCell Cycle/ C12H12ClN3 [1] Natoni, A [1] http://w No Development ReportedApoptosis C11H9NO2S2DMSO: ≥ 33 [1] Young SH,[1] http://w No Development ReportedProtein Tyro C12H6Cl2O2 10 mM in D [1] Kundu S, [1] https:// No Development ReportedNF-κB C14H17N5 10 mM in D [1] Burke JR, [1] http://w No Development ReportedMAPK/ERK PaC18H24O 10 mM in D [1] Chen Z, e[1] http://w Phase 2Autophagy; C12H7N3O2SDMSO: 5.8 m[1] Huang X, [1] https:// No Development ReportedAutophagy; EC9H14N4O5 DMSO: ≥ 30 [1] http://w Phase 3Apoptosis; A C13H13N3OSDMSO: ≥ 46 [1] Degterev [1] http://w No Development ReportedJAK/STAT Sig C13H13NO3SDMSO: ≥150[1] Xia Z, et [1] https:// No Development ReportedAnti-infecti C14H19NO4 10 mM in D [1] http://w No Development ReportedAutophagy; C18H18O2 10 mM in D [1] http://w No Development ReportedAutophagy; C16H13NO3 DMSO: 16 mg[1] Reiners J [1] http://w No Development ReportedProtein Tyro C16H12O4 DMSO: ≥ 35 [1] Liu XJ, e [1] http://w No Development ReportedAutophagy; C15H10O5 DMSO: ≥ 30 [1] Lim W, et[1] http://w No Development ReportedAutophagy; CC15H10O5 DMSO: 9.4 m [1] https:// No Development ReportedAutophagy; J C15H10O5 DMSO: ≥ 33 [1] Peterson [1] http://w Phase 4PI3K/Akt/mT C13H14N6O DMSO: 16 m [1] Mirzoeva [1] http://w Phase 2Autophagy; J C15H12O5 DMSO: ≥ 35 [1] Er-Bin Ya [1] www.ncb No Development ReportedPI3K/Akt/mTOC9H9BrN2O3DMSO: ≥ 42 [1] Rozhon W,[1] http://w No Development Reported

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[4] Lim S, et al. Targeting of the MNK-eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function. Proc Natl Acad Sci U S A. 2013 Jun 18;110(25):E2298-307.

DMSO: ＜ 9 mg/mL

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JAK/STAT Sig C11H6F3NO210 mM in D [1] Lin YW, B [1] http://w No Development ReportedJAK/STAT Sig C14H8Cl2N2 DMSO: ≥ 26 [1] Yoneda T,[1] https:// No Development ReportedProtein Tyro C17H13N3O [1] Wood ER,[1] http://w No Development ReportedApoptosis C17H12N2O210 mM in D [1] Okamoto M[1] http://w No Development ReportedPI3K/Akt/mT C18H16N2O DMSO: ≥ 34 [1] Cusimano [1] http://w No Development ReportedPI3K/Akt/mTOC16H11N3O2DMSO: ≥ 37 [1] Leclerc S [1] http://w No Development ReportedNF-κB C12H10FN3O10 mM in D [1] Sachse F,[1] http://w No Development ReportedCell Cycle/ C16H15N3O2DMSO: 6 mg [1] Ballou LM[1] https:// No Development ReportedProtein Tyro C16H19N5 [1] Hanke JH,[1] https:// No Development ReportedPI3K/Akt/mT C15H14N4O2DMSO: ≥ 27 [1] https:// No Development ReportedProtein Tyro C18H22N2O 10 mM in D [1] Park SJ, [1] http://w No Development ReportedProtein Tyro C6H14Cl4N4 H2</s[1] Hochwald [1] http://w No Development ReportedAutophagy; C16H12O5 DMSO: ≥ 48 [1] He L, et [1] http://w No Development ReportedMAPK/ERK PaC15H24O5 10 mM in D [1] Chen Q, e[1] http://w Phase 4Autophagy; PC15H10O6 DMSO: ≥ 30 [1] https://w No Development ReportedAutophagy; EC5H12N2O8PH2</su[1] Berenson,[1] http://w LaunchedNF-κB C14H18ClN5 10 mM in D [1] Burke JR, [1] http://w No Development ReportedCell Cycle/ C16H16N6 10 mM in D [1] Cuny, Gre[1] http://w No Development ReportedImmunology/IC17H19N5 DMSO: 12.2 [1] Buckley G[1] http://w No Development ReportedAutophagy; J C17H14N2O310 mM in D [1] http://w No Development ReportedApoptosis; E C17H26O4 DMSO: 10 m [1] Radhakris[1] https:// No Development ReportedProtein Tyro C17H16N2O3DMSO: ≥ 30 [1] Sun L, et [1] http://w No Development ReportedCell Cycle/ C18H19NO3 10 mM in D [1] Yuan J, e [1] http://w No Development ReportedMAPK/ERK PaC16H12FN3S10 mM in D [1] Griswold [1] http://w No Development ReportedProtein Tyro C16H14N2O4DMSO: ≥ 47 [1] Hasegawa,[1] http://w No Development ReportedNF-κB C16H14N2O4DMSO: ≥ 36 [1] http://w LaunchedAutophagy; CC14H11N3O310 mM in D [1] Park H, e [1] http://w No Development ReportedProtein Tyro C15H16ClN5 10 mM in D No Development ReportedAutophagy; CC15H10O7 10 mM in D [1] Navarro-N[1] https:// Phase 4Immunology/C15H11ClN2 DMSO: ≥ 34 [1] Liu H, et [1] https:// No Development ReportedProtein Tyro C20H20N2O DMSO: 10 m [1] Wang L, e[1] http://w No Development ReportedAutophagy; PC14H13BrN210 mM in D [1] Párrizas [1] http://w No Development ReportedPI3K/Akt/mT C14H8FNO4SDMSO: ≥ 57 [1] Pomel V, [1] http://w No Development ReportedCell Cycle/ C13H16NNaODMSO: 6.4 mg[1] Xie XQ, [1] https:// No Development ReportedImmunology/IC17H14N4O210 mM in DMSO No Development ReportedAutophagy; CC19H17NO3 DMSO: 14.9 [1] Chaussade[1] http://w No Development ReportedCell Cycle/D C14H17N3O3DMSO: ≥ 31 [1] Tsutomu A[1] http://j LaunchedPI3K/Akt/mTOC12H12N4O410 mM in D [1] http://w No Development ReportedCell Cycle/ C16H12FN5ODMSO: ≥ 30 [1] WO20141[1] http://w No Development ReportedAutophagy; C15H15N7O 10 mM in D [1] http://w Phase 2Protein Tyro C18H18N2O3DMSO: ≥ 28 [1] http://w Phase 3Cell Cycle/D C18H17NO4 DMSO: ≥ 33 [1] Behrend L[1] http://w No Development ReportedCell Cycle/D C15H13N5OSDMSO: ≥ 30 [1] Zhu J, Pa [1] http://w No Development Reported

DMSO: ＜ 11.2 mg/mL

DMSO: ≥ 28 mg/mL (Need ultrasonic)[1] Islam I, et al. Indolinone based phosphoinositide-dependent kinase-1 (PDK1) inhibitors. Part 2: optimization of BX-517. Bioorg Med Chem Lett. 2007 Jul 15;17(14):3819-25. [2] Islam I, et al. Indolinone based phosphoinositide-dependent kinase-1 (PDK1) inhibitors. Part 1: design, synthesis and biological activity. Bioorg Med Chem Lett. 2007 Jul 15;17(14):3814-8.

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PI3K/Akt/mT C17H16ClN3 10 mM in D [1] http://w Phase 1Neuronal Sig C19H10N2O3DMSO: 5.6 mg[1] Tokumitsu[1] https:// No Development ReportedAutophagy; J C16H14ClN3 10 mM in D [1] Bojko A, [1] https:// No Development ReportedMAPK/ERK PaC16H12O7 DMSO: ≥ 28 mg/mL No Development ReportedJAK/STAT Sig C18H24N2OSDMSO: ≥ 30 [1] Rende M e[1] http://w No Development ReportedCell Cycle/D C16H13ClN2 DMSO: ≥ 45 [1] Lee JW, [1] http://w No Development ReportedProtein Tyro C19H19N5 DMSO: 14.25[1] Bishop AC[1] http://w No Development ReportedAutophagy; PC18H14N4O210 mM in D [1] Kordes e [1] http://w No Development ReportedPI3K/Akt/mTOC17H17N7 10 mM in D [1] Apsel B, [1] http://w No Development ReportedAutophagy; C17H17N7 DMSO: ≥ 31 [1] Honda A, [1] https:// No Development ReportedCell Cycle/D C14H23Cl2N DMSO: ≥ 32 [1] Ishizaki [1] https:// No Development ReportedAnti-infecti C13H16N6O4DMSO: ≥ 44 [1] http://w Phase 2Protein Tyro C13H12N4O2DMSO: 5.625[1] Zhang S, [1] http://w No Development ReportedNF-κB C17H11ClN4 DMSO: ≥ 43 [1] Cho J, et [1] http://w No Development ReportedMAPK/ERK PaC18H29ClN2 10 mM in D [1] Laskin, J [1] http://w LaunchedCell Cycle/ C14H13Cl2N DMSO: 3.4 mg[1] Koltun ES[1] http://w No Development ReportedCell Cycle/D C16H14N4O210 mM in D [1] Patel RA, [1] http://w No Development ReportedCell Cycle/D C16H11BrN2DMSO: ≥ 35 [1] Lyssiotis [1] http://w No Development ReportedMAPK/ERK PaC18H13N7 DMSO: ≥ 50 [1] http://w No Development ReportedAutophagy; CC14H18ClN3 DMSO: ≥ 31 [1] https:// LaunchedJAK/STAT Sig C14H12BrN510 mM in D [1] Rewcastle[1] http://w No Development ReportedCell Cycle/D C16H14N2O2DMSO: ≥ 51 [1] Golub AG,[1] http://w No Development ReportedAutophagy; C20H14FN3ODMSO: ≥ 40 [1] Davies SP[1] http://w No Development ReportedCell Cycle/ C20H21N5 DMSO: 27.5 [1] Larochell [1] http://w No Development ReportedProtein Tyro C20H20N4O 10 mM in D [1] Shiotsu Y [1] http://w Phase 1MAPK/ERK PaC20H16N2OSDMSO: ≥ 51 [1] Angell RM[1] http://w No Development ReportedProtein Tyro C16H19N3O5DMSO: 15.5 [1] National [1] Phase 2PI3K/Akt/mT C18H11N3O210 mM in D [1] https:// Phase 1Protein Tyro C16H13ClFN 10 mM in D [1] Han SY, P[1] http://w No Development ReportedMAPK/ERK PaC19H18N4O210 mM in D [1] Wong H, e[1] http://w No Development ReportedPI3K/Akt/mTOC19H14N2O2DMSO: 12.5 [1] Domínguez[1] http://w Phase 2MAPK/ERK PaC16H12F3N310 mM in D [1] Radwanska[1] http://w No Development ReportedProtein Tyro C18H13FN4O10 mM in D [1] https:// No Development ReportedCell Cycle/ C16H16N8O DMSO: ≥ 32 [1] Mortense [1] http://w No Development ReportedPI3K/Akt/mT C20H20ClN3 10 mM in D [1] Grimshaw[1] http://w No Development ReportedProtein Tyro C15H21N3O6DMSO: ≥ 29 [1] https:// No Development ReportedJAK/STAT Sig C20H13N5O 10 mM in D [1] Bamborou[1] http://w No Development ReportedProtein Tyro C20H16N6 DMSO: ≥ 42 [1] Tiedt, Ra [1] http://w No Development ReportedProtein Tyro C18H24N6O H2</s[1] Reilly MP [1] https:// No Development ReportedCell Cycle/ C18H17ClN4 DMSO: ≥125[1] Czodrowsk[1] https:// No Development ReportedProtein Tyro C18H16ClN3 10 mM in D [1] Gable KL,[1] http://w No Development ReportedAutophagy; C18H20ClN5 10 mM in D [1] Yap TA et[1] http://w No Development ReportedImmunology/C19H34ClNO10 mM in D [1] Rolin J, [1] http://w Launched

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Epigenetics; C19H36O5 10 mM in D [1] Pinkosky [1] http://w Phase 3Cell Cycle/ C18H17F2N310 mM in D [1] Misra RN,[1] http://w No Development ReportedProtein Tyro C18H15N2NaDMSO: ≥ 54 [1] Bono F, e [1] http://w No Development ReportedPI3K/Akt/mT C18H14N6O210 mM in D [1] Doukas J, [1] http://w Phase 2Cell Cycle/ C16H19ClN6 10 mM in D [1] ray NS, W[1] http://w No Development ReportedAutophagy; C20H14ClN3 DMSO: ≥ 34 [1] Shelton J [1] http://w No Development ReportedEpigenetics; C20H28O5 10 mM in D [1] Hasler CM[1] http://w No Development ReportedCell Cycle/ C17H15N7O2DMSO: 7 mg/[1] Rainey MD[1] http://w No Development ReportedCell Cycle/ C18H18F3N3DMSO: ≥ 42 [1] Fukuhara [1] http://w No Development ReportedAutophagy; CC19H12ClN3 DMSO: ≥ 35 [1] http://w Phase 2Cell Cycle/D C20H14O2S210 mM in D [1] http://w No Development ReportedCell Cycle/D C20H12F3N310 mM in D [1] Laco F, e [1] http://w No Development ReportedCell Cycle/ C18H13N3OSDMSO: ≥ 47 [1] Vassilev [1] http://w No Development ReportedProtein Tyro C19H20ClN5 DMSO: ≥ 73 [1] Tandon M,[1] http://w No Development ReportedPI3K/Akt/mT C17H22N8O 10 mM in D [1] JA Pachte [1] http://w Phase 1Cell Cycle/ C19H26N6O 10 mM in D [1] http://w Phase 2Protein Tyro C19H21N3O2DMSO: ≥ 38 [1] Na YJ, et [1] https:// No Development ReportedCell Cycle/D C19H14ClNODMSO: 10.75 [1] http://e No Development ReportedEpigenetics; C18H18ClN5 10 mM in D [1] Kuo GH, D[1] http://w No Development ReportedCell Cycle/D C16H10BrN3DMSO: ≥ 23 [1] https:// No Development ReportedAutophagy; EC9H17N4O9P10 mM in H [1] http://w Phase 3Protein Tyro C20H16N6O DMSO: ≥ 31 [1] Nakanishi[1] https:// No Development ReportedProtein Tyro C18H14ClFN DMSO: ≥ 53 [1] Tovar C, [1] http://w No Development ReportedEpigenetics; C23H19NO3 DMSO: ≥ 38 [1] Muranaka [1] http://w No Development ReportedProtein Tyro C18H22N4O4DMSO: ≥ 28 [1] Nicolas [1] http://w No Development ReportedProtein Tyro C18H13N7S DMSO: ≥ 3.6[1] Buchanan [1] http://w Phase 1PI3K/Akt/mTOC16H10ClN3 10 mM in D [1] Pizarro J [1] http://w No Development ReportedCell Cycle/D C11H8Br2N2DMSO: ≥ 42 [1] Mahajan S[1] http://w No Development ReportedJAK/STAT Sig C16H14BrN310 mM in D [1] Fry DW, e[1] http://w No Development ReportedAutophagy; C20H13FN4O10 mM in D [1] Fu Y, et [1] http://w No Development ReportedEpigenetics; C20H12N2O3DMSO: 24 m [1] Cool B, e [1] http://w No Development ReportedProtein Tyro C18H20N2O410 mM in D [1] Patch RJ, [1] http://w No Development ReportedImmunology/IC18H20FN3ODMSO: ≥ 33 [1] Seganish [1] https:// No Development ReportedCell Cycle/ C19H31N5O210 mM in D [1] Locatelli [1] http://w Phase 1Epigenetics; C13H14BrCl DMSO: ≥ 46 [1] Zhang LN,[1] http://w No Development ReportedCell Cycle/ C17H19FN4O10 mM in D [1] Zabludoff[1] http://w Phase 1PI3K/Akt/mT C19H17N5O3DMSO: 6.4 mg[1] Yap TA, e[1] http://w Phase 2Cell Cycle/ C20H14ClN3 DMSO: ≥ 55 [1] Arienti K [1] http://w No Development ReportedCell Cycle/ C18H19ClFN 10 mM in D [1] Keith B P [1] http:// No Development ReportedMetabolic En C18H18F2N2DMSO [1] Ackermann[1] https:// No Development ReportedPI3K/Akt/mT C15H17FN6ODMSO: ≥ 53 [1] http://w No Development ReportedPI3K/Akt/mT C21H24N4O210 mM in D [1] Zhao Y, e[1] https:// No Development ReportedPI3K/Akt/mT C17H17ClN2 10 mM in D [1] http://w No Development Reported

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Cell Cycle/D C19H16FN5ODMSO: ≥ 30 [1] Waldschmi[1] https:// No Development ReportedProtein Tyro C20H22N4O3DMSO: 17.5 [1] http://w No Development ReportedNF-κB C19H15ClN4 DMSO: ≥ 31 [1] Hideshima[1] http://w No Development ReportedJAK/STAT Sig C18H11BrN2DMSO: ≥ 52 [1] Cheney IW[1] http://w No Development ReportedCell Cycle/D C22H14FN5 DMSO: ≥ 26 [1] APTO-253 [1] http://a Phase 1Autophagy; C20H14ClNO10 mM in DM[1] Afseth J, [1] http://w No Development ReportedMAPK/ERK PaC21H18F2N2DMSO: ≥ 32 [1] Aronchik [1] http://w No Development ReportedMAPK/ERK PaC20H21FN4O10 mM in D [1] Bison S, [1] http://w No Development ReportedCell Cycle/ C18H16N4O310 mM in D [1] Reaper PM[1] https:// No Development ReportedAutophagy; J C17H13BrN4DMSO: ≥ 30 [1] Fry DW et[1] http://w No Development ReportedProtein Tyro C23H19N3O210 mM in D [1] Munshi N,[1] http://w Phase 3Autophagy; PC19H19FN4ODMSO: ≥ 50 [1] Bhide RS,[1] http://w Phase 3Protein Tyro C19H18N2O4DMSO: ≥ 30 [1] Rohatgi N[1] https:// No Development ReportedCell Cycle/ C18H18N4O3DMSO: ≥ 47 [1] Albert TK [1] http://w No Development ReportedAutophagy; PC19H12Cl2N 10 mM in D [1] Gurrieri, [1] http://w No Development ReportedProtein Tyro C23H21N3O210 mM in D [1] http://w No Development ReportedProtein Tyro C19H21N3O3DMSO: 18.5 [1] Blake RA,[1] http://w No Development ReportedCell Cycle/ C18H21N5O210 mM in D [1] Byth KF, [1] http://w Phase 1Autophagy; CC19H11ClN3 10 mM in D [1] http://w Phase 2Protein Tyro C19H16N8O 10 mM in D [1] Timofeevs[1] http://w Phase 1Autophagy; C21H24O6 DMSO: ≥ 3.6[1] Kang N, [1] http://w No Development ReportedCell Cycle/D C23H24N4O DMSO: 26.5 [1] William A [1] http://w Phase 2PI3K/Akt/mT C17H16N4O2DMSO: ≥ 28 [1] Anastasio[1] http://w No Development ReportedCell Cycle/ C16H17ClN8 DMSO: ≥ 30 [1] Mortense [1] http://w No Development ReportedProtein Tyro C22H19N3O3DMSO: 6.2 mg[1] Tian G, e [1] https:// No Development ReportedProtein Tyro C22H23N5O DMSO: ≥ 30 [1] Polverino [1] http://w Phase 3Protein Tyro C18H13F3N4DMSO: ≥ 45 [1] Adrián FJ [1] http://w No Development ReportedAutophagy; PC21H18FN5O10 mM in D [1] Albert DH[1] http://w Phase 3Epigenetics; C16H14BrN3DMSO: ≥ 47 [1] Sareila O [1] http://w No Development ReportedProtein Tyro C19H13F2N7DMSO: ≥ 30 [1] Perera T, [1] [2] htt Phase 1PI3K/Akt/mTOC22H20FN3ODMSO: ≥ 54. [1] Schmole [1] http://w No Development ReportedPI3K/Akt/mT C15H19N7O310 mM in D [1] Tanaka H,[1] http://w Phase 1Autophagy; C21H16FN3ODMSO: ≥ 33 [1] Lali FV, [1] http://w No Development ReportedMetabolic En C18H22N2O310 mM in D [1] Fenner D,[1] http://w No Development ReportedCell Cycle/ C16H16F3N7DMSO: ≥ 32 [1] Osborne J[1] https:// No Development ReportedMAPK/ERK PaC13H9N5O5SDMSO: ≥ 31 [1] Stebbins [1] www.ncb No Development ReportedJAK/STAT Sig C21H21N3O2DMSO: 28.5 [1] Dakin LA,[1] http://w Phase 1PI3K/Akt/mT C18H13FN6ODMSO: ≥ 29 [1] Liu KK, e [1] http://w No Development ReportedCell Cycle/D C21H20N2O3DMSO: ≥ 300 mg/mL No Development ReportedCell Cycle/ C17H24N4O210 mM in D [1] Chen R, e[1] https:// Phase 1JAK/STAT Sig C18H13BrN4DMSO: 13.67[1] Discafani [1] http://w No Development ReportedMAPK/ERK PaC22H21F2N3DMSO: ≥ 31 [1] Aronchik No Development ReportedAutophagy; CC19H23N7O210 mM in D [1] https:// Phase 2

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Protein Tyro C21H17F3N4DMSO: ≥ 31 [1] Zhang C, [1] http://w No Development ReportedMetabolic En C25H22N2O2DMSO: ≥ 40. [1] Sherk AB,[1] http://w No Development ReportedJAK/STAT Sig C19H14FN3ODMSO: ≥ 28 [1] Jia Y et [1] http://w No Development ReportedAutophagy; C22H26FN3ODMSO: ≥ 58 [1] Willette [1] http://w Phase 3NF-κB C15H8ClF6N 10 mM in D [1] Hosokawa [1] http://w No Development ReportedAutophagy; EC21H18ClNODMSO: ≥ 3.9 [1] http://h No Development ReportedAutophagy; CC19H18BrN3DMSO: ≥ 33 [1] Bartholo [1] https:// No Development ReportedPI3K/Akt/mT C19H17ClN4 DMSO: 4.1 m[1] Raynaud F[1] https:// No Development ReportedImmunology/C18H25ClN2 10 mM in D [1] Liu K, et [1] http://w No Development ReportedPI3K/Akt/mT C21H16FN7 10 mM in D [1] Cushing T[1] http://w No Development ReportedMAPK/ERK PaC22H19N5O2DMSO: 10 m [1] Norman P,[1] https:// No Development ReportedApoptosis; M C24H26N4O 10 mM in D [1] Allen JE, [1] http://w No Development ReportedApoptosis; M C24H26N4O 10 mM in D [1] Allen JE, [1] http://w Phase 2MAPK/ERK PaC23H21N3O3DMSO: ≥ 33 [1] Dhawan NS[1] https:// No Development ReportedJAK/STAT Sig C18H19ClFN DMSO: ≥ 41 [1] Solca FF, [1] http://w Phase 1Protein Tyro C20H15ClF2 10 mM in D [1] Rational [1] http://w No Development ReportedAutophagy; C19H25ClN6 10 mM in D [1] Gray NS, [1] http://w No Development ReportedCell Cycle/ C19H14F3N3DMSO: ≥ 36 [1] Rak R, et [1] https:// No Development ReportedMAPK/ERK PaC23H23N3O310 mM in D [1] Hall-Jack [1] http://w No Development ReportedPI3K/Akt/mT C14H16ClN3 10 mM in D [1] https:// No Development ReportedMAPK/ERK PaC19H21F3N610 mM in D [1] Pearce LR[1] http://w No Development ReportedAutophagy; C19H23F2N510 mM in D [1] Sapkota G[1] http://w No Development ReportedMetabolic En C11H13IN4ODMSO: ≥ 49 [1] Massillon [1] http://w No Development ReportedAutophagy; EC21H27Cl2N DMSO: 6.4 m[1] Bharadwaj[1] http://w LaunchedProtein Tyro C21H21FN6ODMSO: 25 m [1] Trudel S, [1] http://w Phase 3Protein Tyro C21H19N3O5DMSO: 7.75 [1] Sun Q, et [1] http://w No Development ReportedAutophagy; J C22H23N3O410 mM in D [1] Moyer JD,[1] http://w LaunchedCell Cycle/D C21H27N7O 10 mM in D [1] D'Alise A [1] http://w No Development ReportedPI3K/Akt/mT C17H23N5O210 mM in D [1] Jamieson [1] http://w No Development ReportedImmunology/IC20H21N5O410 mM in D [1] Powers JP[1] http://w No Development ReportedAutophagy; C21H17NO3SDMSO: 80 mg/[1] Hickson I [1] http://w No Development ReportedProtein Tyro C20H24N6O3DMSO: 10.33[1] Panek RL,[1] https:// No Development ReportedProtein Tyro C22H25FN4O10 mM in D [1] Yancey MF[1] http://w No Development ReportedImmunology/IC20H20N4O310 mM in D [1] Buckley G[1] http://w No Development ReportedCell Cycle/ C21H28N6O2DMSO: ≥ 56 [1] Parry D, [1] http://w Phase 3Apoptosis C22H21ClN2 10 mM in D [1] Sharlow E[1] http://w No Development ReportedPI3K/Akt/mT C22H19N7O 10 mM in D [1] Billottet [1] http://e No Development ReportedAutophagy; CC23H18N4O310 mM in D [1] http://w No Development ReportedApoptosis C20H19FN4ODMSO: ≥ 37 [1] Haile PA [1] http://w No Development ReportedAutophagy; PC22H27FN4ODMSO: 25 m [1] Sun L, et [1] http://w LaunchedProtein Tyro C20H22N4O3DMSO: ≥ 30 [1] Pyonteck [1] http://w No Development ReportedCell Cycle/ C25H25N3O2DMSO: ≥19. [1] Ma Y, et [1] http://w No Development ReportedMAPK/ERK PaC24H21N3OS10 mM in D [1] Miwatashi[1] http://w Phase 2

[1] Chan, et al. Identification of chelerythrine as an inhibitor of BclXL function. J Biol Chem. 2003 Jun 6;278(23):20453-6. [2] Li W, et al. Effect of Chelerythrine Against Endotoxic Shock in Mice and Its Modulation of Inflammatory Mediators in Peritoneal Macrophages Through the Modulation of Mitogen-Activated Protein Kinase (MAPK) Pathway. Inflammation. 2012 Jul 24. [3] Pěn?íková K, et al. Investigation of sanguinarine and chelerythrine effects on LPS-induced inflammatory gene expression in THP-1 cell line. Phytomedicine. 2012 Jul 15;19(10):890-5. Epub 2012 May 14. [4] Chen XM, et al. Chelerythrine chloride induces apoptosis in renal cancer HEK-293 and SW-839 cell lines. Oncol Lett. 2016 Jun;11(6):3917-3924.

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Cell Cycle/ C20H28N6O310 mM in D [1] Graub R, [1] http://w No Development ReportedNF-κB C21H25ClN4 10 mM in D [1] Murata T,[1] http://w No Development ReportedPI3K/Akt/mT C21H16FN7ODMSO: ≥ 29 [1] Shugg RP,[1] https:// No Development ReportedAutophagy; C21H20ClNO10 mM in D [1] Mahoney E[1] http://w Phase 2MAPK/ERK PaC22H24ClNO10 mM in D [1] https:// No Development ReportedMAPK/ERK PaC19H12F4N4DMSO: ≥ 42 [1] Kuliopul [1] http://w Phase 2Autophagy; J C20H22F3N510 mM in D [1] https:// Phase 1Protein Tyro C21H19FN6ODMSO: ≥ 28 [1] http://w Phase 3Cell Cycle/ C23H26N4O310 mM in D [1] https:// Phase 2Protein Tyro C22H21N3O310 mM in D [1] Cazorla M[1] http://w No Development ReportedAutophagy; CC22H24N4O4DMSO: ≥ 43 [1] Feng Y, e [1] http://w No Development ReportedAutophagy; C22H24N4O410 mM in D [1] Nylander [1] http://w Phase 1PI3K/Akt/mT C20H31N3O210 mM in D [1] Meuillet [1] http://w No Development ReportedProtein Tyro C20H16ClN5 DMSO: ≥ 46 [1] Steeghs N[1] http://w Phase 2Cell Cycle/D C19H22Cl2F DMSO: ≥ 32 [1] Daniel I. [1] http://o No Development ReportedPI3K/Akt/mT C18H21F3N610 mM in D [1] Burger MT[1] https:// Phase 3PI3K/Akt/mT C20H22Cl3N 10 mM in D [1] Grimshaw[1] http://w No Development ReportedPI3K/Akt/mT C17H20F3N710 mM in D [1] Cmiljanov[1] No Development ReportedProtein Tyro C23H21N7O DMSO: ≥ 43 [1] Currie KS [1] http://w Phase 2Protein Tyro C22H19ClFN 10 mM in D [1] Whittles [1] http://w No Development ReportedProtein Tyro C16H14BrNODMSO: ≥ 30 [1] Garofalo [1] https:// No Development ReportedProtein Tyro C23H17FN6ODMSO: 12.66[1] Liu X, et [1] http://w Phase 4MAPK/ERK PaC25H24N4O2DMSO: ≥ 45 [1] Li L, et [1] http://w No Development ReportedCell Cycle/ C21H24N4O310 mM in D [1] Foote KM,[1] http://w No Development ReportedCell Cycle/ C20H24N6O2DMSO: ≥ 38 [1] Vendetti [1] https:// No Development ReportedCell Cycle/D C25H19NO3S10 mM in D [1] https:// No Development ReportedMAPK/ERK PaC17H14ClF2 10 mM in D [1] Tsai J, e [1] http://w No Development ReportedAutophagy; C21H17ClFN H2</s[1] Lali FV, [1] http://w No Development ReportedProtein Tyro C22H22O8 10 mM in D [1] Girnita A [1] https:// Phase 2Cell Cycle/ C24H18N2O3DMSO: ≥ 37. [1] Morrison [1] https:// No Development ReportedPI3K/Akt/mT C19H22N6O3DMSO: 20 m [1] Salphati [1] http://w No Development ReportedProtein Tyro C20H23ClN6 DMSO: ≥ 30 [1] Zhang J, [1] https:// No Development ReportedProtein Tyro C21H16F3N310 mM in D [1] Cao ZX, e[1] http://w No Development ReportedAutophagy; C22H18FN7ODMSO: ≥ 59. [1] Lannutti [1] http://w LaunchedMAPK/ERK PatC27H45NO2 [1] Yan KH e [1] http://w No Development ReportedJAK/STAT Sig C21H22ClN3 DMSO: ≥ 4.2[1] Meany HJ,[1] http://w No Development ReportedCell Cycle/ C23H21FN6ODMSO: ≥ 41 [1] Atkins C, [1] http://w No Development ReportedProtein Tyro C20H21ClN4 10 mM in D [1] Nakamura [1] http://w No Development ReportedPI3K/Akt/mT C22H17ClN6 10 mM in DMSO No Development ReportedPI3K/Akt/mT C22H17ClN6 DMSO: ≥ 41 [1] Pillinger [1] https:// Phase 3Autophagy; C19H21F2N710 mM in D [1] Yaguchi S[1] http://w Phase 1Protein Tyro C24H27N5O210 mM in D [1] https:// No Development ReportedProtein Tyro C20H15ClF3 DMSO: ≥ 30 [1] Gelhorn H[1] https:// No Development Reported

[1] Yoo M, et al. Dehydrocorydaline promotes myogenic differentiation via p38 MAPK activation. Mol Med Rep. 2016 Oct;14(4):3029-36. [2] Yin ZY, et al. Antinociceptive effects of dehydrocorydaline in mouse models of inflammatory pain involve the opioid receptor and inflammatory cytokines. Sci Rep. 2016 Jun 7;6:27129. [3] Xu Z, et al. Dehydrocorydaline inhibits breast cancer cells proliferation by inducing apoptosis in MCF-7 cells. Am J Chin Med. 2012;40(1):177-85.

[1] Hou X, et al. Biochemical changes of salivary gland adenoid cystic carcinoma cells induced by SGI-1776. Exp Cell Res. 2017 Mar 15;352(2):403-411. [2] Park YK, et al. The novel anti-adipogenic effect and mechanisms of action of SGI-1776, a Pim-specific inhibitor, in 3T3-L1 adipocytes. Int J Mol Med. 2016 Jan;37(1):157-64. [3] Xie J, et al. SGI-1776, an imidazo pyridazine compound, inhibits the proliferation of ovarian cancer cells by inactivating Pim-1. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2014 Jul;39(7):649-57. [4] Chen LS, et al. Mechanisms of cytotoxicity to Pim kinase inhibitor, SGI-1776, in acute myeloid leukemia. Blood, 2011, 118(3), 693-702. [1] Johnson TW, et al. Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinas [2] Zou HY, et al. PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations. Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3493-8. [3] Zou HY, et al. PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations. Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3493-8. [1] Wei L, et al. Genomic profiling is predictive of response to cisplatin treatment but not to PI3K inhibition in bladder cancer patient-derived xenografts. Oncotarget. 2016 Nov 22;7(47):76374-76389.

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10 mM in DMSO

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Protein Tyro C20H17F3N4DMSO: ≥ 49 [1] Zhang J, [1] http://w No Development ReportedJAK/STAT Sig C22H25F3N4DMSO: 10 m [1] Foulks JM [1] https:// No Development ReportedCell Cycle/ C16H18Cl3N 10 mM in D [1] http://w Phase 2Protein Tyro C20H17Cl3N 10 mM in D [1] Wood JM, [1] http://w Phase 3Cell Cycle/D C23H22ClN5 DMSO: 14 m [1] Tse AN, e[1] http://w No Development ReportedProtein Tyro C26H23N5O 10 mM in D [1] Mulvihill [1] http://w Phase 3Autophagy; C27H27N5 DMSO: ≥ 33 [1] Goodfello[1] http://w No Development ReportedPI3K/Akt/mT C21H18N4O4DMSO: ≥ 26 [1] https:// No Development ReportedProtein Tyro C22H22FN5ODMSO: ≥ 45 [1] Evans EK [1] http://w Phase 2Metabolic En C22H25N5O4DMSO: ≥ 30 [1] Dransfiel [1] https:// No Development ReportedProtein Tyro C22H15F3N4DMSO: ≥ 33 [1] Halin C e [1] www.ncb No Development ReportedCell Cycle/ C22H20N2O510 mM in D [1] Garland L[1] http://w No Development ReportedAutophagy; C23H29FN6ODMSO: ≥ 38 [1] https:// Phase 1MAPK/ERK PaC22H25ClN6 10 mM in D [1] Ma FY, et [1] https:// Phase 1PI3K/Akt/mT C22H27N5O410 mM in D [1] Yuan J, e [1] http://w Phase 2Autophagy; C21H27N7O310 mM in D [1] Rhodes N,[1] http://w Phase 1PI3K/Akt/mT C21H24ClN7 DMSO: ≥ 31 [1] WO/2012 [1] http://w No Development ReportedAutophagy; C20H22N6OSDMSO: ≥ 49 [1] Duncia JV[1] http://w No Development ReportedProtein Tyro C21H19ClN4 10 mM in D [1] Matsui J, [1] http://w LaunchedPI3K/Akt/mTOC18H17Cl2F DMSO: ≥ 40 [1] http://w Phase 2JAK/STAT Sig C22H22ClN3 10 mM in D [1] Tan F, et [1] http://w LaunchedProtein Tyro C21H22F2N6DMSO: ≥ 4.6[1] Nagasubr[1] www.ncbiNo Development ReportedPI3K/Akt/mT C28H44O3 10 mM in DMSO LaunchedAutophagy; MC21H25ClN6 10 mM in D [1] Davies BR[1] http://w Phase 2PI3K/Akt/mT C18H16Cl2F DMSO: ≥ 36 [1] Pachl F, [1] http://w Phase 2Cell Cycle/ C17H12Cl2F DMSO: ≥ 30 [1] www.ncb No Development ReportedCell Cycle/ C24H27N7O 10 mM in D [1] Divakar [1] https:// No Development ReportedProtein Tyro C24H27N7O DMSO: ≥ 30 [1] Ashford [1] http://w No Development ReportedAutophagy; J C22H24ClN3 DMSO: ≥ 4.3[1] Moyer JD,[1] http://w LaunchedProtein Tyro C19H24ClN9 DMSO: ≥ 33 [1] https:// No Development ReportedMAPK/ERK PaC15H15FIN3 10 mM in D [1] Kim K, et [1] http://w Phase 2Cell Cycle/ C17H14Cl2F DMSO: ≥ 34 [1] www.ncbiNo Development ReportedCell Cycle/D C20H19ClFN DMSO: ≥ 34 [1] www.ncb No Development ReportedCell Cycle/D C21H16F4N4DMSO: ≥ 51 [1] Goodman K[1] http://w No Development ReportedCell Cycle/ C23H28N8O DMSO: ≥60 [1] Hutterer [1] https:// No Development ReportedCell Cycle/ C20H25ClN6 DMSO: ≥ 40 [1] purvalano[1] http://p No Development ReportedMAPK/ERK PaC21H22Cl2N DMSO: ≥ 45 mg/mL No Development ReportedPI3K/Akt/mT C22H22F3N3DMSO: 10.6 [1] http://w Phase 2Cell Cycle/D C24H26N4O410 mM in D [1] Xiong Cai[1] http://w Phase 1Cell Cycle/ C23H30N8O DMSO: ≥ 4.3[1] VanArsdal[1] https:// LaunchedCell Cycle/D C6HBr4N3 [1] De Moline[1] http://w No Development ReportedMAPK/ERK PaC19H9Cl2F2 [1] Duffy JP, [1] https:// Phase 2Autophagy; C18H22BrN5DMSO: 29.5 [1] King C, e [1] http://w Phase 2

[1] Alessandri AL, Duffin R, Leitch AE, Lucas CD, Sheldrake TA, Dorward DA, Hirani N, Pinho V, de Sousa LP, Teixeira MM, Lyons JF, Haslett C, Rossi AG. Induction of eosinophil apoptosis by the cyclin-dependent kinase inhibitor AT7519 promotes the resolution of eosinophil-dominant allergic inflammation. PLoS One. 2011;6(9):e25683. [2] Mahadevan D, Plummer R, Squires MS, Rensvold D, Kurtin S, Pretzinger C, Dragovich T, Adams J, Lock V, Smith DM, Von Hoff D, Calvert H. A phase I pharmacokinetic and pharmacodynamic study of AT7519, a cyclin-dependent kinase inhibitor in patients with refractory solid tumors. Ann Oncol. 2011 Sep;22(9):2137-43. [3] Squires MS, Cooke L, Lock V, Qi W, Lewis EJ, Thompson NT, Lyons JF, Mahadevan D. AT7519, a cyclin-dependent kinase inhibitor, exerts its effects by transcriptional inhibition in leukemia cell lines and patient samples. Mol Cancer Ther. 2010 Apr;9(4):920-8. [4] Santo L, Vallet S, Hideshima T, Cirstea D, Ikeda H, Pozzi S, Patel K, Okawa Y, Gorgun G, Perrone G, Calabrese E, Yule M, Squires M, Ladetto M, Boccadoro M, Richardson PG, Munshi NC, Anderson KC, Raje N. AT7519, A novel small molecule multi-cyclin-dependent kinase inhibitor, induces apoptosis in multiple myeloma via GSK-3beta activation and RNA polymerase II inhibition. Oncogene. 2010 Apr 22;29(16):2325-36. [5] Squires MS, Feltell RE, Wallis NG, Lewis EJ, Smith DM, Cross DM, Lyons JF, Thompson NT. Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. Mol Cancer Ther. 2009 Feb;8(2):324-32. [1] Rumman M, et al. HS-173, a novel PI3K inhibitor suppresses EMT and metastasis in pancreatic cancer. Oncotarget. 2016 Oct 25. [2] Son MK, et al. HS-173, a novel PI3K inhibitor, attenuates the activation of hepatic stellate cells in liver fibrosis. Sci Rep. 2013 Dec 11;3:3470. [3] Yun SM, et al. Synergistic anticancer activity of HS-173, a novel PI3K inhibitor in combination with Sorafenib against pancreatic cancer cells. Cancer Lett. 2013 May 1;331(2):250-61.

[1] Vakana E, et al. LY3009120, a panRAF inhibitor, has significant anti-tumor activity in BRAF and KRAS mutant preclinical models of colorectal cancer. Oncotarget. 2017 Feb 7;8(6):9251-9266. [2] Chen SH, et al. Oncogenic BRAF Deletions That Function as Homodimers and Are Sensitive to Inhibition by RAF Dimer Inhibitor LY3009120. Cancer Discov. 2016 Mar;6(3):300-15. [3] Peng SB, et al. Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers. Cancer Cell. 2015 Sep 14;28(3):384-98. [4] Henry JR, et al. Discovery of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a pan-RAF inhibitor with minimal paradoxical activation and activity against BRAF or RAS mutant tumo

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DMSO: ≥ 430 mg/mLDMSO: 13.08 mg/mL (Need ultrasonic)

Autophagy; PC21H23N7O2DMSO: ≥ 43 [1] Harris PA [1] http://w LaunchedCell Cycle/D C22H31N9O 10 mM in D [1] Scagliott [1] http://w Phase 1Autophagy; C21H21Cl2N 10 mM in D [1] Senderowi[1] http://w Phase 2Epigenetics; C25H22N6O210 mM in D [1] https:// Phase 2Protein Tyro C22H22N4O4DMSO: ≥ 31 [1] Burbridge[1] https:// No Development ReportedProtein Tyro C25H24N6O2DMSO: ≥ 52 [1] Honigberg[1] http://w LaunchedMAPK/ERK PaC27H28N4O2DMSO: ≥ 49. [1] Tatake R [1] http://w No Development ReportedJAK/STAT Sig C27H32N6 DMSO: 10 m [1] Traxler P [1] http://w Phase 2Autophagy; C17H15BrF2 10 mM in D [1] J Phenege[1] https:// Phase 3Autophagy; PC22H24FN5O10 mM in D [1] Bhide RS,[1] http://w Phase 3PI3K/Akt/mT C19H22F3N5DMSO: ≥ 40 [1] Furet P, [1] https:// Phase 3Protein Tyro C23H27FN4O10 mM in D [1] Patyna S, [1] http://w No Development ReportedEpigenetics; C26H26N4O3DMSO: ≥ 34 [1] Gschwendt[1] http://w No Development ReportedProtein Tyro C23H27ClN4 DMSO: ≥ 42 [1] Plé PA, e [1] http://w No Development ReportedProtein Tyro C22H16F3N310 mM in D [1] Garton AJ[1] http://w Phase 1Autophagy; PC26H29N5O210 mM in D [1] Heinrich [1] http://w Phase 3Protein Tyro C21H19Cl2N 10 mM in D [1] Zhao G, e[1] http://w Phase 1Epigenetics; C20H27N7O3DMSO: ≥ 30 [1] Guo A, et [1] https:// Phase 2PI3K/Akt/mT C24H26N6O310 mM in D [1] Cheng H [1] www.ncb No Development ReportedProtein Tyro C25H30N6O2DMSO: ≥ 33 [1] Perera TP[1] https:// No Development ReportedPI3K/Akt/mT C18H22ClF3 10 mM in D [1] Burger MT[1] http://p Phase 3Autophagy; J C22H24ClFN DMSO: ≥ 30 [1] Pedersen [1] http://w LaunchedProtein Tyro C24H25N5O4DMSO: ≥ 41 [1] Plé PA, e [1] http://w No Development ReportedProtein Tyro C23H21N5O310 mM in D [1] Bearss DJ[1] http://w Phase 2Autophagy; C21H20O11 DMSO: ≥ 31 [1] Cincin ZB[1] http://w No Development ReportedPI3K/Akt/mT C21H16N6O210 mM in D [1] Patent N [1] http://w No Development ReportedAutophagy; PC24H25ClN6 10 mM in DMSO No Development ReportedAutophagy; PC21H22Cl2F DMSO: 55 mg/ [1] http://w LaunchedAutophagy; PC25H27FN4ODMSO: ≥ 49 [1] Wedge SR,[1] http://w Phase 3Cell Cycle/ C22H24Cl2N DMSO: ≥ 38 [1] Sidrauski [1] http://w No Development ReportedCell Cycle/ C24H20F3N5DMSO: ≥ 31 [1] Axten JM, [1] http://w No Development ReportedMAPK/ERK PaC27H25N5O210 mM in D [1] Khazak V,[1] http://w No Development ReportedProtein Tyro C26H37N5O2DMSO: ≥ 37 [1] Murayama[1] https:// No Development ReportedCell Cycle/D C26H24N6O2DMSO: ≥ 29 [1] Boerma, M[1] http://w No Development ReportedPI3K/Akt/mTOC21H23N7O310 mM in D [1] Marsell R [1] http://w No Development ReportedMAPK/ERK PaC27H27N5O210 mM in D [1] King AJ, [1] http://w No Development ReportedProtein Tyro C25H22N6O310 mM in D [1] Burger JA [1] www.ncbiPhase 1Protein Tyro C22H19ClN4 10 mM in D [1] Nakamura [1] http://w Phase 3Protein Tyro C26H26FN7 DMSO: ≥ 34 [1] Wang X, e[1] https:// No Development ReportedMAPK/ERK PaC16H14FIN4 DMSO: ≥ 30 [1] Hatzivas [1] http://w Phase 1MAPK/ERK PaC22H18F2N410 mM in D [1] Spevak, [1] No Development ReportedProtein Tyro C25H24N6O3DMSO: ≥ 29 [1] Simon Rul[1] http://w No Development ReportedPI3K/Akt/mT C24H25F2N3DMSO: ≥ 35 [1] Hancox U,[1] http://w Phase 1

[1] Evenou JP, et al. The potent protein kinase C-selective inhibitor AEB071 (sotrastaurin) represents a new class of immunosuppressive agents affecting early T-cell activation. J Pharmacol Exp Ther. 2009 Sep;330(3):792-801. [2] Musi E, et al. The phosphoinositide 3-kinase α selective inhibitor BYL719 enhances the effect of the protein kinase C inhibitor AEB071 in GNAQ/GNA11-mutant uveal melanoma cells. Mol Cancer Ther. 2014 May;13(5):1044-53. [3] Kamo N, et al. Sotrastaurin, a protein kinase C inhibitor, ameliorates ischemia and reperfusion injury in rat orthotopic liver transplantation. Am J Transplant. 2011 Nov;11(11):2499-507.

[1] Zou HY, et al. An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res. 2007, 67(9), 4408-4417. [2] Christensen JG, et al. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther. 2007, 6(12 Pt 1), 3314-3322. [3] Sampson ER, et al. The orally bioavailable met inhibitor PF-2341066 inhibits osteosarcoma growth and osteolysis/matrix production in a xenograft model. J Bone Miner Res. 2011, 26(6), 1283-1294. [4] Cullinane C, et al. Differential (18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine PET responses to pharmacologic inhibition of the c-MET receptor in preclinical tumor models. J Nucl Med. 2011 Aug;52(8):1261-7.

MAPK/ERK PaC25H23N5O210 mM in D [1] https:// No Development ReportedMAPK/ERK PaC17H15BrCl DMSO: ≥ 34 [1] Huynh H, [1] http://w LaunchedPI3K/Akt/mT C24H32ClN5 DMSO: ≥ 28 [1] Blake JF, [1] https:// Phase 4JAK/STAT Sig C22H23ClFN 10 mM in D [1] Zeng Q, [1] https:// No Development ReportedCell Cycle/ C17H19Cl2N 10 mM in D [1] McMillin [1] http://w No Development ReportedPI3K/Akt/mT C24H28N8O210 mM in D [1] Zachary S[1] http://w Phase 3Autophagy; C25H32N8O 10 mM in D [1] http://w Phase 2MAPK/ERK PaC16H17FIN3 10 mM in D [1] Wallace E[1] http://w Phase 1MAPK/ERK PaC18H15N5O6DMSO: ≥ 28 [1] Steinhart [1] https:// No Development ReportedProtein Tyro C23H24FN9O10 mM in D [1] Carboni J [1] http://w Phase 2Cell Cycle/ C26H31N5O3DMSO: 6.2 mg [1] https:/ No Development ReportedAutophagy; C25H52NO4P10 mM in D [1] Momota H,[1] https:// Phase 4Cell Cycle/D C22H21ClFN DMSO: 6.4 m[1] Shimomura[1] https:// Phase 1JAK/STAT Sig C26H24ClN3 10 mM in D [1] http://p No Development ReportedPI3K/Akt/mT C25H34N8O 10 mM in D [1] https:// No Development ReportedCell Cycle/ C18H15Cl4N 10 mM in D [1] Xia F, et [1] http://w No Development ReportedProtein Tyro C20H20Cl2N DMSO: ≥ 4.6[1] Yamamoto [1] http://w No Development ReportedProtein Tyro C23H22FN7ODMSO: ≥ 30 [1] Paul E. H [1] http://c No Development ReportedCell Cycle/ C24H25N5O3DMSO: ≥ 35 [1] Fokas E, [1] http://w Phase 2Protein Tyro C26H33N5O310 mM in D [1] Gavine PR[1] http://w Phase 3Protein Tyro C25H33N7O2DMSO: ≥ 44 [1] Zhang W, [1] http://w No Development ReportedPI3K/Akt/mTOC18H18Cl3F DMSO: ≥ 52 [1] http://w Phase 2Cell Cycle/D C29H28N4O2DMSO: ≥36 [1] Sini P, e [1] https:// No Development ReportedAutophagy; CC23H28N8OS10 mM in D [1] http://w Phase 2Autophagy; C26H36N6O210 mM in D [1] Clark K, [1] http://w No Development ReportedAutophagy; MC21H16ClF3 DMSO: ≥ 45 [1] Wilhelm S[1] http://w LaunchedAutophagy; PC22H18Cl2N DMSO: ≥ 5.1[1] Ring DB, [1] http://w No Development ReportedProtein Tyro C26H23N7O2DMSO: ≥ 31 [1] https:// No Development ReportedProtein Tyro C22H20BrN510 mM in D [1] Mark L. W[1] www.ncb Phase 2Autophagy; C25H21N7O3 [1] Jefferies [1] http://w No Development ReportedJAK/STAT Sig C24H23ClFN DMSO: 16 m [1] Torrance [1] http://w Phase 2JAK/STAT Sig C25H23F3N410 mM in D [1] Nagasawa [1] http://w Phase 1Protein Tyro C20H20N8O410 mM in D [1] Timofeevs[1] http://w Phase 1Epigenetics; C26H28N8O 10 mM in D [1] Banerjee [1] http://w No Development ReportedProtein Tyro C23H15ClF2 10 mM in D [1] WO20090[1] http:// No Development ReportedProtein Tyro C23H25ClN6 10 mM in D [1] Liu TJ, e [1] http://w No Development ReportedProtein Tyro C24H18F3N310 mM in D [1] Kubo K, e[1] http://w No Development ReportedJAK/STAT Sig C27H27N5O3DMSO: ≥ 50 [1] Jani JP, [1] http://w No Development ReportedPI3K/Akt/mT C22H31N9O3DMSO: 16 m [1] Bernard B[1] http://c No Development ReportedJAK/STAT Sig C24H25ClFN DMSO: ≥ 50 m[1] Engelman [1] http://w Phase 3Epigenetics; C23H25ClFN 10 mM in D [1] Ma L, et [1] http://w Phase 2Protein Tyro C22H23FN6O10 mM in D [1] Braselman[1] http://w No Development ReportedCell Cycle/ C30H22N4O210 mM in D [1] Toledo, L [1] http://w No Development Reported

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[3] Palmer SS, et al. Bentamapimod (JNK Inhibitor AS602801) Induces Regression of Endometriotic Lesions in Animal Models. Reprod Sci. 2016 Jan;23(1):11-23.

[1] Caporali S, Alvino E, Levati L, Esposito AI, Ciomei M, Brasca MG, Del Bufalo D, Desideri M, Bonmassar E, Pfeffer U, D'Atri S. Down-regulation of the PTTG1 proto-oncogene contributes to the melanoma suppressive effects of the cyclin-dependent kinase inhibitor PHA-848125. Biochem Pharmacol. 2012 Sep 1;84(5):598-611. [2] Albanese C, Alzani R, Amboldi N, Avanzi N, Ballinari D, Brasca MG, Festuccia C, Fiorentini F, Locatelli G, Pastori W, Patton V, Roletto F, Colotta F, Galvani A, Isacchi A, Moll J, Pesenti E, Mercurio C, Ciomei M. Dual targeting of CDK and tropomyosin receptor kinase families by the oral inhibitor PHA-848125, an agent with broad-spectrum antitumor efficacy. Mol Cancer Ther. 2010 Aug;9(8):2243-54. [3] Degrassi A, Russo M, Nanni C, Patton V, Alzani R, Giusti AM, Fanti S, Ciomei M, Pesenti E, Texido G. Efficacy of PHA-848125, a cyclin-dependent kinase inhibitor, on the K-Ras(G12D)LA2 lung adenocarcinoma transgenic mouse model: evaluation by multimodality imaging. Mol Cancer Ther. 2010 Mar;9(3):673-81. [4] Caporali S, Alvino E, Starace G, Ciomei M, Brasca MG, Levati L, Garbin A, Castiglia D, Covaciu C, Bonmassar E, D'Atri S. The cyclin-dependent kinase inhibitor PHA-848125 suppresses the in vitro growth of human melanomas sensitive or resistant to temozolomide, and shows synergistic effects in combination with this triazene compound. Pharmacol Res. 2010 May;61(5):437-48. [5] Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy By Albanese, Clara; Alzani, Rachele; Amboldi, Nadia; Avanzi, Nilla; Ballinari, Dario; Brasca, Maria Gabriella; Festuccia, Claudio; Fiorentini, Francesco; Locatelli, Giuseppe; Pastori, Wilma; et al From Molecular Cancer Therapeutics (2010), 9(8), 2243-2254.

[1] Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer.

[1] Mustapha Haddach, Jerome Michaux, Michael K, Discovery of CX-6258. A Potent, Selective, and Orally Efficacious pan-Pim Kinases Inhibitor. ACS Med. Chem. Lett., 2012, 3 (2), pp 135-139 [2] Padmanabhan A, Gosc EB, Bieberich CJ. Stabilization of the prostate-specific tumor suppressor NKX3.1 by the oncogenic protein kinase Pim-1 in prostate cancer cells. J Cell Biochem. 2013 May;114(5):1050-7. [1] Najafov A, et al. Characterization of GSK2334470, a novel and highly specific inhibitor of PDK1. Biochem J. 2011 Jan 15;433(2):357-69. [2] Qi L, et al. PDK1-mTOR signaling pathway inhibitors reduce cell proliferation in MK2206 resistant neuroblastoma cells. Cancer Cell Int. 2015 Sep 29;15:91. [3] Scortegagna M, et al. Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten(-/-) melanoma. Oncogene. 2014 Aug 21;33(34):4330-9.

[1] Dumble M, et al. Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor. PLoS One. 2014 Jun 30;9(6):e100880.

[1] Harrington EA, Bebbington D, Moore J, et al. VX-680, a potent and selective smallmolecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med. 2004; 10:262-7. [2] Salah E, et al. Crystal structures of ABL-related gene (ABL2) in complex with imatinib, tozasertib (VX-680), and a type I inhibitor of the triazole carbothioamide class.J Med Chem. 2011 Apr 14;54(7):2359-67. Epub 2011 Mar 18. [3] Arlot-Bonnemains Y, et al. Effects of the Aurora kinase inhibitor VX-680 on anaplastic thyroid cancer-derived cell lines. Endocr Relat Cancer. 2008 Jun;15(2):559-68.

[1] Herman SE, et al. The Bruton's tyrosine kinase (BTK) inhibitor acalabrutinib demonstrates potent on-target effects and efficacy in two mouse models of chronic lymphocytic leukemia. Clin Cancer Res. 2016 Nov 30. [2] Wu J, et al. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol. 2016 Mar 9;9:21.

DMSO: ≥ 47 mg/mL

Autophagy C25H35ClN6 H2</s[1] Petheric [1] https:// No Development ReportedPI3K/Akt/mT C20H23BrN810 mM in D [1] Feldman R[1] http://w No Development ReportedMAPK/ERK PaC21H18FN5O10 mM in D [1] Wada M, [1] http://w No Development ReportedAutophagy; EC24H27Cl2N H2</su[1] Zhou G, [1] http://w No Development ReportedCell Cycle/ C21H24NNaOH2</s [1] http://w Phase 3JAK/STAT Sig C23H25ClFN DMSO: ≥ 33 [1] Hickinson[1] http://w No Development ReportedAutophagy; PC21H24ClN7 DMSO: 6.4 m[1] Harris PA [1] http://w LaunchedCell Cycle/D C23H25F3N6DMSO: ≥ 47 [1] http://w Phase 1MAPK/ERK PaC26H30N6O310 mM in D [1] Yang Q, [1] http://w No Development ReportedAutophagy; CC26H30N6O3DMSO: 7.5 m [1] https:// Phase 2Autophagy; PC22H24BrFN DMSO: 27.5 [1] Wedge SR,[1] http://w LaunchedProtein Tyro C28H40N6O DMSO: 33.33[1] Zhang W,[1] http://w No Development ReportedCell Cycle/D C9H7Br4N3 10 mM in D [1] Yde CW, e[1] http://w No Development ReportedCell Cycle/ C22H18F3N310 mM in D [1] Lansing e[1] http://w No Development ReportedMAPK/ERK PaC17H14ClF2 DMSO: ≥ 15 [1] Allen LF, [1] https:// Phase 2Metabolic En C19H18ClF3 DMSO: ≥ 46 [1] Morrell J [1] http://w No Development ReportedMAPK/ERK PaC26H19ClN8 DMSO: ≥ 53 [1] Wang X, e[1] http://w No Development ReportedCell Cycle/ C23H28ClFN 10 mM in D [1] Anderson [1] http://w No Development ReportedAutophagy; C24H28Cl2N DMSO: ≥ 42 [1] Keppner S[1] http://w No Development ReportedAutophagy; C21H17Cl3N DMSO: ≥ 50 [1] Drexler H[1] https:// No Development ReportedProtein Tyro C23H25ClF3 DMSO: ≥125[1] Karpov AS[1] https:// No Development ReportedProtein Tyro C25H26ClN5 10 mM in D [1] Wittman M[1] http://w No Development ReportedAutophagy; C25H23Cl2N DMSO [1] Zhao YY, [1] http://w Phase 2JAK/STAT Sig C26H24N8O210 mM in D [1] Moulder- [1] https:// Phase 1Autophagy; C16H14F3IN DMSO: ≥ 56 [1] Barrett S [1] http://w Phase 2Protein Tyro C24H27FN6ODMSO: ≥ 30 [1] Trudel S, [1] https:// LaunchedProtein Tyro C30H34N4O2DMSO: 6.2 m[1] Sakamoto [1] http://w LaunchedAutophagy; PC21H15ClF4 DMSO: ≥ 26 [1] Wilhelm S[1] http://w Launched NF-κB C28H29N5OSDMSO: ≥ 27 [1] Waelchli [1] http://w No Development ReportedCell Cycle/ C24H30ClN7 DMSO: 6 mg/m[1] Fry DW, e[1] http://w LaunchedNF-κB C24H29ClN6 DMSO: ≥ 37 [1] Deng C, e[1] http://w No Development ReportedJAK/STAT Sig C27H31N7O2DMSO: ≥ 28 mg/mL No Development ReportedAutophagy; J C24H25ClFN 10 mM in D [1] Li D, et [1] http://w LaunchedPI3K/Akt/mTOC20H17Cl2N DMSO: 11 m [1] Ring DB, [1] http://w No Development ReportedJAK/STAT Sig C26H26N6O2DMSO: ≥ 44 [1] https:// No Development ReportedAutophagy; PC21H23Cl3F DMSO: ≥ 4.6 [1] http://w LaunchedAutophagy; PC22H26ClN7 DMSO: 35.35[1] O'Hare T, [1] http://w LaunchedProtein Tyro C18H23Ca0. H2</s[1] Sharifzad [1] http://w LaunchedCell Cycle/ C16H15BrCl 10 mM in D [1] Zheng Z, [1] http://w No Development ReportedProtein Tyro C26H21F2N5DMSO [1] Daniel L. [1] https:/ Phase 1PI3K/Akt/mT C28H23N7O2DMSO: ≥ 40 [1] Knight ZA[1] http://w No Development ReportedAutophagy; C23H18ClF2 DMSO: 6.2 m[1] Bollag G, [1] http://w LaunchedCell Cycle/D C25H30N8OS10 mM in D [1] http://w No Development Reported

[1] Gumireddy K, et al. ON01910, a non-ATP-competitive small molecule inhibitor of Plk1, is a potent anticancer agent. Cancer Cell. 2005 Mar;7(3):275-86. [2] Reddy MV, et al. Discovery of a clinical stage multi-kinase inhibitor sodium (E)-2-{2-methoxy-5-[(2',4',6'-trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON 01910.Na): synthesis, structure-activity relationship, and biological activity. J Med Chem. [3] Chapman CM, et al. ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res. 2012 Apr 1;18(7):1979-91. [1] Sch?ffski P, Jones SF, Dumez H, Infante JR, Van Mieghem E, Fowst C, Gerletti P, Xu H, Jakubczak JL, English PA, Pierce KJ, Burris HA. Phase I, open-label, multicentre, dose-escalation, pharmacokinetic and pharmacodynamic trial of the oral aurora kinase inhibitor PF-03814735 in advanced solid tumours. Eur J Cancer. 2011 Oct;47(15):2256-64. [2] Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2008 Sep;30(7):543-88. [3] Hook KE, Garza SJ, Lira ME, Ching KA, Lee NV, Cao J, Yuan J, Ye J, Ozeck M, Shi ST, Zheng X, Rejto PA, Kan JL, Christensen JG, Pavlicek A. An integrated genomic approach to identify predictive biomarkers of response to the aurora kinase inhibitor PF-03814735. Mol Cancer Ther. 2012 Mar;11(3):710-9. Epub 2012 Jan 5. [4] Jani JP, Arcari J, Bernardo V, Bhattacharya SK, Briere D, Cohen BD, Coleman K, Christensen JG, Emerson EO, Jakowski A, Hook K, Los G, Moyer JD, Pruimboom-Brees I, Pustilnik L, Rossi AM, Steyn SJ, Su C, Tsaparikos K, Wishka D, Yoon K, Jakubczak JL. PF-03814735, an orally bioavailable small molecule aurora kinase inhibitor for cancer therapy. Mol Cancer Ther. 2010 Apr;9(4):883-94.

[1] Zi D, et al. Danusertib Induces Apoptosis, Cell Cycle Arrest, and Autophagy but Inhibits Epithelial to Mesenchymal Transition Involving PI3K/Akt/mTOR Signaling Pathway in Human Ovarian Cancer Cells. Int J Mol Sci. 2015 Nov 13;16(11):27228-51. [2] Gontarewicz A, et al. Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I. Blood. 2008 Apr 15;111(8):4355-64. [3] Fraedrich K, et al. Targeting Aurora Kinases with Danusertib (PHA-739358) Inhibits Growth of Liver Metastases from Gastroenteropancreatic Neuroendocrine Tumors in an Orthotopic Xenograft Model. Clin Cancer Res. 2012 Sep 1;18(17):4621-32. Epub 2012 Jul 2.

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JAK/STAT Sig C23H21Cl2F 10 mM in D [1] Nam HJ, e[1] http://w Phase 2Protein Tyro C18H23N5NaH2</su[1] Sharifzad [1] http://w LaunchedProtein Tyro C22H20F3N5DMSO: ≥ 51 [1] Slack-Dav[1] http://w No Development ReportedAutophagy; PC29H28N6O2DMSO: 27 m [1] Bladt F, [1] http://w Phase 2Autophagy; PC25H27N5O4DMSO: ≥ 32 [1] Tian S, e [1] http://w LaunchedAutophagy; PC29H31N7O [1] http://w LaunchedProtein Tyro C22H28FN4O10 mM in D [1] Yancey MF[1] http://w LaunchedJAK/STAT Sig C25H27ClN6 10 mM in D [1] Zhou W, e[1] http://w No Development ReportedCell Cycle/ C18H18Cl2F 10 mM in D [1] Santo L, [1] http://w Phase 2Epigenetics; C25H29ClN6 DMSO: 24.5 [1] http://w No Development ReportedCell Cycle/D C23H25ClN8 10 mM in D [1] Chan F e [1] http://w No Development ReportedPI3K/Akt/mT C23H30N8O310 mM in D [1] Sutherlin [1] http://w Phase 2Protein Tyro C28H30N6OSDMSO: ≥ 26 [1] http://w Phase 3Protein Tyro C26H22FN7ODMSO: ≥ 45. [1] Akinleye [1] http://w No Development ReportedAnti-infecti C26H21N5O410 mM in D [1] http://w No Development ReportedJAK/STAT Sig C28H33N7O2DMSO: ≥ 30 [1] Cross DA,[1] http://w LaunchedMAPK/ERK PaC24H20Cl2F 10 mM in D [1] Aronov, A[1] http://p No Development ReportedCell Cycle/ C27H32N8O210 mM in D [1] Hirai H, [1] http://w Phase 2Autophagy; PC21H17ClF4 10 mM in D [1] Wilhelm S[1] http://w LaunchedProtein Tyro C25H26F3N5DMSO: ≥ 34 [1] Tanjoni I [1] http://w Phase 1Protein Tyro C28H24FN3ODMSO: ≥ 30 [1] You WK, [1] http://w LaunchedCell Cycle/D C28H35N7O2DMSO: ≥ 30 [1] Soncini C [1] http://w No Development ReportedProtein Tyro C26H20F3N710 mM in D [1] Martiny- [1] http://w No Development ReportedCell Cycle/D C28H21N7OS10 mM in D [1] Payton M,[1] http://w No Development ReportedMAPK/ERK PaC17H15F2IN DMSO: ≥ 33 [1] Erika von [1] http://w Phase 1Cell Cycle/D C28H32N4O310 mM in D [1] http://cl [1] http://cl Phase 1PI3K/Akt/mT C25H17F2N510 mM in D [1] http://p Phase 1MAPK/ERK PaC17H12Cl2F 10 mM in D [1] Elizabeth [1] http://m Phase 1PI3K/Akt/mT C27H31FN6ODMSO [1] Ali K, et [1] http://w No Development ReportedCell Cycle/D C26H30FN7O10 mM in D [1] Wilkinson[1] https:// Phase 3MAPK/ERK PaC29H29N7O2DMSO: ≥ 35 [1] http://w No Development ReportedCell Cycle/D C30H33N7O 10 mM in D [1] Hardwick [1] http://e Phase 1Protein Tyro C26H22Cl2N DMSO: 17 m [1] Hagel M, [1] http://w No Development ReportedAutophagy; EC26H35N7O210 mM in D [1] http://w No Development ReportedProtein Tyro C20H21F3N8DMSO: ≥ 39 [1] Kang Y, e [1] http://w Phase 2PI3K/Akt/mTOC28H25FN6ODMSO: ≥ 31 [1] Zamek-Gli[1] http://w Phase 2Protein Tyro C25H19ClF2 DMSO: ≥ 39 [1] Schroeder[1] http://w Phase 2MAPK/ERK PaC27H30ClFN 10 mM in D [1] Hideshim [1] www.ncb Phase 2Protein Tyro C28H41ClN6 DMSO: 6.66 m[1] Zhang W,[1] http://w No Development ReportedCell Cycle/D C25H23Cl2F [1] Wang Y, e[1] https:// No Development ReportedMAPK/ERK PaC27H24FN7ODMSO: ≥ 32 [1] Girotti M No Development ReportedCell Cycle/D C29H31N5O410 mM in D [1] Ditchfiel [1] http://w No Development ReportedAutophagy; C23H27N7O3DMSO: ≥ 29 [1] Wallin JJ [1] http://w Phase 2

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Autophagy; EC32H29N5O210 mM in D [1] Rovedo MA[1] http://w Phase 3Protein Tyro C24H30ClN7 DMSO: ≥ 30 [1] Mollard A [1] http://w No Development ReportedPI3K/Akt/mT C28H22F2N410 mM in DMSO No Development ReportedAutophagy; CC29H32N4O310 mM in D [1] Hauf S, C [1] http://w No Development ReportedMAPK/ERK PaC24H22F3N510 mM in D [1] James J, [1] http://w Phase 1Protein Tyro C26H20FN5O10 mM in D [1] Claridge [1] https:// No Development ReportedProtein Tyro C23H28ClN7 10 mM in D [1] A Dose F [1] http://c No Development ReportedAutophagy; MC24H16F6N6DMSO: ≥ 26 [1] AACR Meet[1] http://w Phase 2Autophagy; CC27H20ClFN DMSO: 9.33 [1] Güllü G, [1] http://w Phase 3Protein Tyro C30H35ClN4 DMSO: 6 mg/m[1] Sakamoto [1] http://w LaunchedAutophagy; PC21H16Cl2F DMSO: ≥ 5.6[1] Wilhelm S[1] http://w LaunchedAutophagy; PC20H22BrCl DMSO: ≥ 50 [1] Chijiwa T [1] http://w No Development ReportedMAPK/ERK PaC23H20F3N5DMSO: ≥ 33 [1] Greger JG[1] http://w LaunchedMAPK/ERK PaC15H8Br2IN 10 mM in D [1] http://w No Development ReportedCell Cycle/D C28H39N7O310 mM in D [1] Lénárt P, [1] https:// Phase 2MAPK/ERK PaC26H44NNaOH2</s[1] Kim SY, [1] http://w LaunchedProtein Tyro C28H41N7O3DMSO: ≥ 52 [1] Mohammadi[1] http://w No Development ReportedAutophagy; PC22H27Cl2N DMSO: 15 m [1] O'Hare T, [1] http://w LaunchedCell Cycle/D C25H31N7O610 mM in D [1] Fletcher [1] http://w Phase 2Cell Cycle/D C19H19ClN6 10 mM in D [1] Zhang B, [1] http://w Phase 1Cell Cycle/D C27H33N3O6DMSO: ≥ 57 [1] Lau GM, e[1] http://w No Development ReportedMAPK/ERK PaC31H37N5O310 mM in D [1] http://w Phase 2PI3K/Akt/mT C30H24N8O2DMSO: 15 m [1] Evans CA,[1] https:// No Development ReportedProtein Tyro C26H34ClN6 10 mM in D [1] Sen Zhan[1] http://ca No Development ReportedAutophagy; PC28H22F3N7DMSO: 28 m [1] http://w LaunchedProtein Tyro C26H30F3N710 mM in D [1] Akeno-Stu[1] http://w No Development ReportedProtein Tyro C31H30N8O 10 mM in D [1] Martin, M [1] http://w No Development ReportedPI3K/Akt/mT C24H34Cl3N H2</s[1] Blake JF, [1] https:// Phase 3MAPK/ERK PaC21H21F3IN 10 mM in D [1] Hoeflich [1] http://w LaunchedCell Cycle/ C24H27F3N8DMSO: 21 m [1] Beria I, [1] http://w Phase 1Protein Tyro C29H27F3N610 mM in D [1] Ren X, Pa[1] http://w No Development ReportedAutophagy; PC29H27F3N6DMSO: ≥ 50 [1] O'Hare T, [1] http://w LaunchedProtein Tyro C27H29FN8O10 mM in D [1] http://w No Development ReportedCell Cycle/ C33H34N4O3DMSO: ≥ 166[1] Mason JM [1] https:// No Development ReportedProtein Tyro C28H21F4N5DMSO: ≥ 32 [1] Albaugh, [1] http://w No Development ReportedProtein Tyro C31H33N5O410 mM in D [1] Hilberg F [1] http://w LaunchedPI3K/Akt/mT C25H25ClN6 DMSO: 6 mg [1] Geoffrey [1] http://w Phase 2Autophagy; PC27H32ClN5 DMSO: ≥ 32 [1] Green TP,[1] http://w Phase 3Cell Cycle/ C27H28F3N510 mM in D [1] https:// Phase 1JAK/STAT Sig C26H27F4N7DMSO: ≥ 52 [1] http://c No Development ReportedProtein Tyro C28H24F3N7DMSO: ≥ 33 [1] Choi HG, [1] https:// No Development ReportedCell Cycle/ C30H33N3O5DMSO: ≥ 30 [1] Golding S[1] http://w No Development ReportedJAK/STAT Sig C26H25ClF3 10 mM in D [1] Ishikawa [1] http://w Phase 1

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MAPK/ERK PaC27H25F3N8DMSO: ≥ 33 [1] Mertins S [1] https:// No Development ReportedCell Cycle/D C26H31BrN810 mM in D [1] http://w No Development ReportedPI3K/Akt/mT C34H29N7O 10 mM in D [1] http://w No Development ReportedProtein Tyro C30H22F2N6DMSO: ≥ 32 [1] Yan SB, e[1] http://w Phase 2Protein Tyro C30H31F3N4DMSO: ≥ 41 [1] Kim HG, e[1] http://w No Development ReportedCell Cycle/ C27H36N8O510 mM in D [1] VanArsdal[1] https:// LaunchedProtein Tyro C30H28FN7O10 mM in D [1] Chan WW, [1] http://w Phase 1Epigenetics; C26H27N5O510 mM in D [1] McKenna J[1] http://w No Development ReportedCell Cycle/D C27H18F4N410 mM in D [1] Okaniwa M[1] http://w No Development ReportedJAK/STAT Sig C27H28F3N7DMSO: ≥ 43 [1] Walter A [1] http://w Phase 3Cell Cycle/ C23H18Cl3F 10 mM in D [1] Alao JP, [1] http://w No Development ReportedJAK/STAT Sig C30H29ClN6 DMSO: 6.4 mg[1] Rabindran[1] http://w No Development ReportedProtein Tyro C28H36ClN5 DMSO: 5.6 mg[1] Marsilje [1] http://w LaunchedProtein Tyro C27H31FN4O10 mM in D [1] Patyna S, [1] http://w No Development ReportedJAK/STAT Sig C24H27Cl3F 10 mM in D [1] Smaill JB [1] http://w Phase 2Protein Tyro C26H31Cl2N DMSO: 27 m [1] Guagnano [1] http://w No Development ReportedProtein Tyro C30H26F2N4DMSO: ≥ 42 [1] Paolino M[1] http://w No Development ReportedAutophagy; PC31H34F2N6DMSO: ≥ 31 [1] Ardini E, [1] https:// LaunchedAutophagy; PC29H32N6O4DMSO: ≥ 33 [1] Zarrinkar [1] http://w Phase 3MAPK/ERK PaC16H13BrF3 10 mM in D [1] Ohren JF, [1] http://w No Development ReportedCell Cycle/ C27H34F3N7DMSO: ≥ 35 [1] Hikichi Y [1] http://w Phase 1Protein Tyro C29H29F3N8DMSO: ≥ 32 [1] Luo H, et [1] http://w Phase 3Protein Tyro C31H42N6O4DMSO: ≥ 36 [1] Kelly LM, [1] http://w Phase 2Cell Cycle/ C31H28ClN7 DMSO: ≥ 27 [1] https:// No Development ReportedAutophagy; PC29H31FN4ODMSO: ≥ 45 [1] Wedge SR,[1] http://w Phase 3JAK/STAT Sig C27H28ClFN 10 mM in D [1] Wong TW, [1] http://w Phase 1Autophagy; PC28H30ClN5 10 mM in D [1] Wang X, e[1] http://w No Development ReportedProtein Tyro C32H36N6O4DMSO: ≥ 46. [1] Martin MW[1] http://w No Development ReportedProtein Tyro C22H29N5O910 mM in D [1] Polverino [1] http://w Phase 3Cell Cycle/D C29H30N8O5 [1] Doe C, et [1] http://w No Development ReportedCell Cycle/ C27H38N8O610 mM in D [1] VanArsdal[1] https:// LaunchedPI3K/Akt/mT C31H24F3N510 mM in D [1] http://w Phase 3MAPK/ERK PaC19H20F3IN DMSO: ≥ 31 [1] Iverson C [1] http://w Phase 2Cell Cycle/ C26H35N7O6H2</s[1] Fry DW, e[1] http://w LaunchedAutophagy; PC22H21Cl5N DMSO: ≥ 32 [1] Ring DB, [1] http://w No Development ReportedAutophagy; PC30H31F3N8DMSO: ≥ 42 [1] Grace MS,[1] http://w Phase 2Protein Tyro C33H44FN5OMOSO: 300 [1] Sullivan [1] https:// No Development ReportedAutophagy; PC34H37N5O410 mM in D [1] http://w No Development ReportedProtein Tyro C30H38ClN7 DMSO: ≥ 41 [1] http://w Phase 1Protein Tyro C29H40N8O310 mM in D [1] Sadao Ku [1] http://ca Phase 1Autophagy; J C29H26ClFN DMSO: ≥ 39 [1] http://w LaunchedAutophagy; PC28H25ClF3 DMSO: ≥ 33 [1] http://w LaunchedProtein Tyro C29H39ClN7 10 mM in Eth [1] https:// Launched

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[1] Di Paolo, Julie A. et al. Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis. Nature Chemical Biology (2011), 7(1), 41-50 [2] Kokabee L, et al. Bruton's tyrosine kinase is a potential therapeutic target in prostate cancer. Cancer Biol Ther. 2015;16(11):1604-15. [1] From PCT Int. Appl. (2013), WO 2013134353 A1 20130912. [2] Salem I, et al. The effects of CEP-37440, an inhibitor of focal adhesion kinase, in vitro and in vivo on inflammatory breast cancer cells. Breast Cancer Res. 2016 Mar 24;18(1):37.

[1] Rusnak DW, et al. The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther. 2001 Dec;1(2):85-94. [2] O'Neill F, et al. Gene expression changes as markers of early lapatinib response in a panel of breast cancer cell lines. Mol Cancer. 2012 Jun 18;11(1):41. [3] Eryilmaz U, et al. S100A1 as a Potential Diagnostic Biomarker for Assessing Cardiotoxicity and Implications for the Chemotherapy of Certain Cancers. PLoS One. 2015 Dec 18;10(12):e0145418. [1] Weisberg E, et al. Beneficial effects of combining nilotinib and imatinib in preclinical models of BCR-ABL+ leukemias. Blood. 2007 Mar 1;109(5):2112-20. [2] Sako H, et al. Antitumor effect of the tyrosine kinase inhibitor Nilotinib on gastrointestinal stromal tumor (GIST) and Imatinib-resistant GIST cells. PLoS One. 2014 Sep 15;9(9):e107613. [3] Dervis Hakim G, et al. Mucosal healing effect of nilotinib in indomethacin-induced enterocolitis: A rat model. World J Gastroenterol. 2015 Nov 28;21(44):12576-85. [1] Zhang S, et al. The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models. Clin Cancer Res. 2016 Nov 15;22(22):5527-5538. [2] Huang WS, et al. Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase. J Med Chem. 2016 May 26;59(10):4948-64. [3] Siaw JT, et al. Brigatinib, an anaplastic lymphoma kinase inhibitor, abrogates activity and growth in ALK-positive neuroblastoma cells, Drosophila and mice. Oncotarget. 2016 May 17;7(20):29011-22.

Cell Cycle/D C26H31FN7ODMSO: ≥ 33 [1] Yang J, e [1] http://w Phase 3Cell Cycle/D C31H31ClFN 10 mM in D [1] Aliagas-M[1] http://w No Development ReportedAutophagy; PC30H35N7O4DMSO: ≥ 49 [1] http://w LaunchedPI3K/Akt/mT C23H26IN7O10 mM in D [1] Feldman R[1] http://w No Development ReportedProtein Tyro C29H37Cl3N H2</s[1] Wilson MB[1] http://w No Development ReportedProtein Tyro C29H34N6O4DMSO: ≥ 30 [1] http://w Phase 3JAK/STAT Sig C29H37N7O510 mM in D [1] Cross DA,[1] http://w LaunchedPI3K/Akt/mT C31H29N5O6DMSO: 27.5 mg/mL No Development ReportedCell Cycle/ C31H29Cl2N DMSO: 22.5 [1] https:// No Development ReportedCell Cycle/ C28H36F2N8H2</s[1] Ku BM, et[1] http://w Phase 3JAK/STAT Sig C30H30FN7ODMSO: ≥300[1] Xu X, et [1] https:// No Development ReportedProtein Tyro C30H37ClN8 10 mM in D [1] Park CH, [1] http://w No Development ReportedProtein Tyro C19H20F3N7DMSO: ≥ 41. [1] Jarvis A, [1] http://w No Development ReportedProtein Tyro C28H36O15 DMSO: ≥ 31 [1] Choi JM, [1] https:// No Development ReportedMAPK/ERK PaC26H37FN6O [1] Mader M, [1] http://w Phase 2Protein Tyro C30H40ClN7 10 mM in D [1] Galkin AV[1] http://w No Development ReportedMAPK/ERK PaC26H23FIN5 10 mM in D [1] Yamaguchi[1] http://w LaunchedMAPK/ERK PaC24H24F3N5DMSO: ≥ 36 [1] Greger JG[1] http://w LaunchedMAPK/ERK PaC28H27F4N7DMSO: 10.25[1] Phung TL,[1] http://w No Development ReportedCell Cycle/ C34H50N8O310 mM in D [1] Xie FF, e [1] https:// Phase 3JAK/STAT Sig C36H62O8 [1] http://ww No Development ReportedEpigenetics; C29H36O15 DMSO: ≥ 6.3[1] Dell'aqui [1] http://w No Development ReportedProtein Tyro C28H29FN6ODMSO: ≥ 61 [1] Braselman[1] http://w No Development ReportedProtein Tyro C33H29F2N5DMSO: ≥ 32 [1] Patwardha[1] www.ncb No Development ReportedProtein Tyro C28H38Cl3N H2</s[1] Marsilje [1] http://w LaunchedCell Cycle/ C27H27F2N7DMSO: 8.5 m[1] Wong YL, [1] http://w No Development ReportedProtein Tyro C34H34F2N4DMSO: ≥ 38 [1] Qian F, e [1] http://w Phase 2Cell Cycle/ C26H25F2N7DMSO: ≥ 31 [1] Wong YL. [1] https:// No Development ReportedProtein Tyro C33H37F2N710 mM in D [1] Nakagawa[1] http://w Phase 2Protein Tyro C35H38N8O4DMSO: ≥ 30 [1] Tan L, et [1] http://w No Development ReportedProtein Tyro C29H39ClN6 DMSO: ≥ 6.4[1] Cheng M, [1] http://w No Development ReportedProtein Tyro C32H30FN3ODMSO: ≥ 23 [1] You WK, e[1] http://w LaunchedJAK/STAT Sig C27H29BrF3 DMSO: ≥ 59 [1] Walter A [1] http://w Phase 3Autophagy; MC28H24ClF3 DMSO: ≥ 31 [1] Wilhelm S[1] http://w LaunchedMAPK/ERK PaC36H46N8O310 mM in D [1] Elkins, J [1] http://p No Development ReportedAutophagy; PC32H34Cl2N 10 mM in D [1] Christens [1] http://w No Development ReportedAutophagy; C37H31N5O410 mM in D [1] Maira SM,[1] http://w Phase 2Protein Tyro C33H39N5O710 mM in D [1] Hilberg F [1] http://w LaunchedAutophagy; C32H29F3N610 mM in D [1] Baumann [1] http://w No Development ReportedCell Cycle/ C37H38N4O7DMSO [1] Sampson P[1] https:// No Development ReportedProtein Tyro C30H33F3N810 mM in D [1] Luo H, et [1] http://w Phase 3Protein Tyro C27H26F3N7DMSO: 21.4 [1] Roberts W[1] http://w No Development ReportedAutophagy; C33H40O15 DMSO: ≥ 34 [1] Li L, et [1] http://w Phase 3

[1] Heinrich MC, et al. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood. 2000 Aug 1;96(3):925-32. [2] Guida T, et al. Sorafenib inhibits imatinib-resistant KIT and platelet-derived growth factor receptor beta gatekeeper mutants. Clin Cancer Res. 2007 Jun 1;13(11):3363-9. [3] Okuda K, et al. ARG tyrosine kinase activity is inhibited by STI571.Blood. 2001 Apr 15;97(8):2440-8. [4] Maj E, et al. Vitamin D Analogs Potentiate the Antitumor Effect of Imatinib Mesylate in a Human A549 Lung Tumor Model. Int J Mol Sci. 2015 Nov 13;16(11):27191-207. [5] Tanaka S, et al. Protective Effects of Imatinib on Ischemia/Reperfusion Injury in Rat Lung. Ann Thorac Surg. 2016 Jul 23. pii: S0003-4975(16)30523-9.

[1] Dubreuil P, et al. Masitinib (AB1010), a Potent and Selective Tyrosine Kinase Inhibitor Targeting KIT. PLoS One, 2009, 4(9), e7258. [2] Lawrence J, et al. Masitinib demonstrates anti-proliferative and pro-apoptotic activity in primary and metastatic feline injection-site sarcoma cells. Vet Comp Oncol, 2011, doi: 10.1111/j.1476-5829.2011.00291.x. [3] Hahn KA, et al. Masitinib is safe and effective for the treatment of canine mast cell tumors. J Vet Intern Med, 2008, 22(6), 1301-1309. [4] Humbert M, et al. Masitinib combined with standard gemcitabine chemotherapy: in vitro and in vivo studies in human pancreatic tumour cell lines and ectopic mouse model. PLoS One. 2010 Mar 4;5(3):e9430.

[1] Kwiatkowski N, et al. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature. 2014 Jul 31;511(7511):616-20. [2] Jiang YY, et al. Targeting super-enhancer-associated oncogenes in oesophageal squamous cell carcinoma. Gut. 2016 May 10. pii: gutjnl-2016-311818. [3] Christensen CL, et al. Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell. 2014 Dec 8;26(6):909-22. [4] Chipumuro, et al. CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer. Cell. 2014 Nov 20;159(5):1126-39.

DMSO: ＜ 7.8 mg/mL

DMSO: ≥ 300 mg/mL[1] Yan Zhu, et al. Ginsenoside Rh2 suppresses growth of uterine leiomyoma in vitro and in vivo and may regulate ERα/c-Src/p38 MAPK activity. Journal of Functional Foods Volume 18, Part A, October 2015, Pages 73–82 [2] Shaoyi Li, et al. Ginsenoside Rh2 inhibits invasiveness of glioblastoma through modulation of VEGF-A. Tumor Biology July 2015 [3] Ning Guan, et al. Ginsenoside Rh2 inhibits metastasis of glioblastoma multiforme through Akt-regulated MMP13. Tumor Biology, April 2015 [4] Zhou J, et al. Ginsenoside Rh2 Suppresses Neovascularization in Xenograft Psoriasis Model. Cell Physiol Biochem 2015;36:980-987

MAPK/ERK PaC28H29FIN5 [1] Yamaguchi[1] http://w LaunchedProtein Tyro C28H29ClF2 DMSO: ≥ 31 [1] Robert M.[1] http:// No Development ReportedAutophagy; C25H35N7O910 mM in D [1] Wallin JJ [1] http://w Phase 2Autophagy; J C32H33ClFN DMSO: ≥ 35 [1] http://w LaunchedMembrane TraC38H35N5O610 mM in D [1] Gargett C[1] http://w No Development ReportedProtein Tyro C23H24FN6NDMSO: 31.81[1] Braselman[1] http://w Phase 3MAPK/ERK PatC41H68O14 [1] https:// No Development ReportedProtein Tyro C44H47F2N910 mM in D [1] Sabbatini [1] http://w No Development ReportedAutophagy; J C43H42ClFN 10 mM in D [1] http://w Launched

DMSO: ≥ 69 mg/mL (Need ultrasonic)

[1] Li D, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene. 2008 Aug 7;27(34):4702-11. [2] Wong CH, et al. Preclinical evaluation of afatinib (BIBW2992) in esophageal squamous cell carcinoma (ESCC). Am J Cancer Res. 2015 Nov 15;5(12):3588-99.

DMSO: ≥ 390 mg/mL (Need ultrasonic)

[1] Li M, et al. Astragaloside IV attenuates cognitive impairments induced by transient cerebral ischemia and reperfusion in mice via anti-inflammatory mechanisms. Neurosci Lett. 2016 Dec 20. pii: S0304-3940(16)30994-6 [2] He CS, et al. Astragaloside IV Enhances Cisplatin Chemosensitivity in Non-Small Cell Lung Cancer Cells Through Inhibition of B7-H3. Cell Physiol Biochem. 2016;40(5):1221-1229. Epub 2016 Dec 14.

[3] Liu L, et al. [Protective effect of astragaloside IV against acute liver failure in experimental mice]. Zhonghua Gan Zang Bing Za Zhi. 2016 Oct 20;24(10):772-777. [4] Jiang K, et al. Astragaloside IV inhibits breast cancer cell invasion by suppressing Vav3 mediated Rac1/MAPK signaling. Int Immunopharmacol. 2016 Dec 5;42:195-202 [1] Rusnak DW, et al. The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther. 2001 Dec;1(2):85-94. [2] O'Neill F, et al. Gene expression changes as markers of early lapatinib response in a panel of breast cancer cell lines. Mol Cancer. 2012 Jun 18;11(1):41. [3] Eryilmaz U, et al. S100A1 as a Potential Diagnostic Biomarker for Assessing Cardiotoxicity and Implications for the Chemotherapy of Certain Cancers. PLoS One. 2015 Dec 18;10(12):e0145418.

Research AreaCancerInflammation/ImmunologCancerCancerCancerInflammation/ImmunologCancerCardiovascular DiseaseCancerCancerInflammation/ImmunologCancerCancerInflammation/ImmunologCancerOthersCancerCancerCancerCancerInfectionCancerCancerCancerCancerInflammation/ImmunologCancerCancerCancerCancerCancerCancerInfectionCancerCancerCancerInflammation/ImmunologCancerCancerCancerCancerOthers

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CancerMetabolic DiseaseCancerOthersCancerCancerCancerNeurological DiseaseCancerNeurological DiseaseCancerCancerCancerCancerNeurological DiseaseCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCardiovascular DiseaseCancerCancerCancerNeurological DiseaseCancerCancerCancerCancerNeurological DiseaseCancerCancerCancerCancerCancerCancerInflammation/Immunolog

Metabolic DiseaseCancerCancerCardiovascular Disease; CancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerInflammation/ImmunologOthersCancerCancerCancerCancerCancerCardiovascular DiseaseCancerCancerMetabolic DiseaseCancerCancerCancerOthersCancerInflammation/ImmunologCancerMetabolic DiseaseCancerCancerCancerCancerMetabolic DiseaseInflammation/ImmunologCancerCancer

Cardiovascular DiseaseInflammation/ImmunologCancerCancerCancerOthersCancerInflammation/ImmunologCancerCancerCancerCancerNeurological DiseaseCancerNeurological DiseaseCancerCancerCancerCancerCancerOthersCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerInflammation/ImmunologMetabolic DiseaseCancerCancerCancerCancerCancerCancerCancerCancerCancer

CancerCancerCancerInflammation/ImmunologCancerInflammation/ImmunologCancerCancerCancerCancerInflammation/ImmunologCancerCancerCancerCancerMetabolic DiseaseCancerCancerCancerCancerCancerCancerCancerNeurological DiseaseCancerCancerCancerCancerCancerInflammation/ImmunologCancerCancerCancer; Cardiovascular DInflammation/ImmunologCancerCancerCancerCancerEndocrinologyCancerCancerCancerInflammation/Immunolog

CancerInflammation/ImmunologCancerCancerCancerInflammation/ImmunologCancerCancerCancerNeurological DiseaseCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerInflammation/ImmunologCancerCancerCancerCancerCancerCancerInflammation/ImmunologCancerCancerCancerCancerCancerCancerCancerCancer

CancerCancerCancerCancerCancerCancerNeurological DiseaseCancerCancerMetabolic DiseaseEndocrinologyCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerEndocrinologyCancerCancerInflammation/ImmunologCancerCancerCancerCancerCancerInflammation/ImmunologCancerCancerInfectionCancerCancerCancerCancerCancerCancerInflammation/ImmunologCancer

CancerCancerCancerInflammation/ImmunologCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerInflammation/ImmunologCancerCancerCancerCancerNeurological DiseaseCancerCancerNeurological DiseaseCancerNeurological DiseaseCancerCancerCancerCancerCancerCancerCancerCancer

CancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerInflammation/ImmunologCancerCancerCancerCardiovascular DiseaseCancerCancerCancerInflammation/ImmunologCancerCancerCancerCardiovascular DiseaseCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerInflammation/ImmunologCancer

CancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerMetabolic DiseaseCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerInflammation/ImmunologCancerCancerCancerCancerMetabolic DiseaseCancerCancerCancerOthersCancerCancerCancerCancerCancer

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CancerCancerCancerCancerCancerCancerCancerCardiovascular DiseaseCancerCancerCancerOthersCancerCancerCancerCancerCancerCancerCancerCancerCancerInflammation/ImmunologCancerCancerCancerCancerInflammation/ImmunologCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancer

CancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerInflammation/ImmunologCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCardiovascular DiseaseCancerCancerCancerCancerCancerCancerCancerInflammation/ImmunologCancerCancerCancerCancerCancer

CancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerInflammation/ImmunologCancerCancerCancerCancerCancerCancerOthersCancer

No Development ReportedCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerCancerInflammation/Immunolog

CancerCancerCancerCancerMetabolic DiseaseInflammation/ImmunologCancerCancerCancer

Biological Description3-Methyladenine is a selective PI3K inhibitor with IC50 of 25 μM and 60 μM for Vps34 and PI3Kγ, respectively, and it can inhibit all PtdIns3Ks at 10 mM.

Metformin (hydrochloride) is a first-line drug for the treatment of type 2 diabetes and there is increasing evidence of a potential efficacy of this agent as an anti-cancer drug.

Trapidil is a vasodilator, is an antiplatelet drug with specific platelet-derived growth factor.

Danthron is a synthetic anthraquinone derivative, currently used as an antioxidant in synthetic lubricants, in the synthesis of antitumor agents, as a fungicide and as an intermediate for making dyes.

Phenformin (hydrochloride) is a hydrochloride salt of phenformin that is an anti-diabetic drug from the biguanide class, can activate AMPK activity.

TG003 is a potent inhibitor of Clk1/Sty; inhibits Clk1 and Clk4 with IC50 values of 20 and 15 nM, respectively.

TPI-1 is a SHP-1 inhibitor; inhibits recombinant SHP-1 with an IC50 of 40 nM.

AS-605240 is a specific and orally active inhibitor of the PI3Kγ, with IC50 of 8 nM, and Ki of 7.8 nM.AICAR is an activator of AMP-activated protein kinase (AMPK), down-regulates the insulin receptor expression in HepG2 cells.

SMI-16a is a selective Pim kinase inhibitor with IC50 values of 0.15, 0.02 and 48 μM for Pim1, Pim2 and PC3 cells, respectively.

Honokiol is a hydroxylated biphenyl compound, which inhibits the activation of Akt and enhances the phosphorylation of ERK1/2.PD98059 is an MEK inhibitor with IC50 of 5 μM, also suppresses TCDD binding to the aryl hydrocarbon receptor (AHR) with IC50 of 4 μM.

Emodin is a broad-spectrum anticancer agent. Emodin inhibits casein kinase II (CKII) activity with IC50 of 2 μM.

5-Aminosalicylic acid is an anti-inflammatory compound.Target: PGE synthase5-aminosalicylic acid (5-ASA), also known as mesalamine or Mesalazine is an anti-inflammatory drug used to treat inflammatory bowel disease, such as ulcerative colitis and mild-to-moderate Crohn's disease. Mesalazine is a bowel-specific aminosalicylate drug that acts locally in the gut and has its predominant actions there, thereby having few systemic side effects. As a derivative of salicylic acid, mesalazine is also thought to be an antioxidant that traps free radicals, which are potentially damaging byproducts of metabolism. Mesalazine is the active moiety of sulfasalazine, which is metabolized to sulfapyridine and mesalazine. Mesalazine is the active component of the prodrug balsalazide along with the inert carrier molecule 4-aminobenzoyl-beta-alanine [1][2].The phosphoserine/phosphothreonine recognition site of the polo-box domain of polo-like kinase 1 is the binding pocket for thymoquinone and its analogue poloxime. Both small molecules displace phosphopeptides bound with the polo-box domain in a slow but noncovalent binding mode.IC50 value:Target:Poloxime displaces phosphopeptides bound with the polo-box domain in a slow but noncovalent binding mode.

AG-18(RG-50810; Tyrphostin A23) inhibits EGFR with IC50 of 40 μM.IC50 Value: 40 uM (inhibition of EGFR autophosphorylation)[1]Target: EGFRAG-18 (Tyrphostin A23) are inhibitors of tyrosine kinases and function by binding to the active sites of the enzymes. Molecular modeling of tyrphostin A23 into the tyrosine-binding pocket in mu2 provides a structural explanation for A23 being able to inhibit the interaction between YXXPhi motifs and mu2. in vitro: A23 inhibited the internalization of (125)I-transferrin in Heb7a cells without having any discernible effect on the morphology of compartments of the endocytic pathway. Control tyrphostins, active as inhibitors of tyrosine kinase activity, but incapable of inhibiting the YXXPhi motif/mu2 interaction, did not inhibit endocytosis [2]. Tyrphostin A23 inhibits Tfn internalization and redistributes most of hTfR to the plasma membrane [3]. TK-inhibiting A23 reversibly increased membrane conductance under conditions designed to minimize Na+, Ca2+, K+, and Na+-K+ pump currents [4].in vivo: Pretreatment with the tyrosine kinase inhibitor Tyr-23 (50 microM, 10 min) caused a slow 40% increase in baseline [Ca(2+)](i). Tyr-23 attenuated peak and plateau responses to NE, both by approximately 70%. In the absence of extracellular Ca(2+) (0 Ca), Tyr-23 reduced the immediate [Ca(2+)](i) response to NE by approximately 60%, indicative of mobilization of internal stores, and abolished the plateau phase [5].Clinical trial:

Scopoletin has important anti-inflammatory activity by inhibiting the phosphorylation of NF-κB and p38 MAPK. Scopoletin cause significant suppression of sprouting of microvessels in rat aortic explants with IC50 of 0.06 μM. target：NF-κB, p38 [1]In vitro: Scopoletin at a dose of 1 mg/kg is able to significantly reduce cell migration and exudation to the pleural fluid (p < 0.01). Scopoletin at the same dose also decreased the myeloperoxidase and adenosine-deaminase activities and nitric oxide, tumor necrosis factor-α, and interleukin-1β levels.[1] Scopoletin showed remarkable inhibition on tumor growth (34.2 and 94.7% at 100 and 200 mg/kg, respectively). Scopoletin may have strong anti-angiogenic effect by inhibiting ERK1, VEGF-A, and FGF-2.[2]In vivo: Scopoletin significantly reduce p65 and p38 phosphorylation in the mouse lungs.[1] Scopoletin (100 and 200 mg/kg) strongly inhibited (59.72 and 89.4%, respectively) vascularization in matrigel plugs implanted in nude mice. [2]

MNS is a potent and selective inhibitor of Src and Syk tyrosine kinases. target: src, syk. [1]IC50:29.3 (src), 2.5 uM (syk); [1]In vitro: no direct effects on protein kinase C, Ca2+ mobilization, Ca2+-dependent enzymes, PKC activation. MNS potently prevents GPIIb/IIIa activation and platelet aggregation without directly affecting other signaling pathways required for platelet activation. [1] [2] MNS is much more potent than genistein in inhibiting platelet aggregation and protein tyrosine phosphorylation. [2]CID755673 is a potent and selective PKD1 inhibitor with an IC50 of 182 nM.SP600125 is a broad-spectrum JNK inhibitor for JNK1, JNK2 and JNK3 with IC50 of 40 nM, 40 nM and 90 nM, respectively.RIPA-56 is a highly potent, selective, and metabolically stable inhibitor of receptor-interactingprotein 1 (RIP1) with an IC50 of 13 nM.

TDZD-8(NP 01139) is a selective inhibitor of GSK-3, a thiadiazolidinone derivative, non-ATP competitive inhibitor of GSK-3β (IC50 = 2 μM); does not inhibit Cdk-1/cyclin B, CK-II, PKA or PKC at >100 μM.IC50 Value: 2 uM (GSK3β)Target: GSK-3βin vitro: Prophylactic or therapeutic administration of TDZD-8 caused the phosphorylation (Ser(9)) and hence inactivation of GSK-3beta. Infarct volume and levels of S100B protein, a marker of cerebral injury, were reduced by TDZD-8. This was associated with a significant reduction in markers of oxidative stress, apoptosis, and the inflammatory response resulting from cerebral I/R [1]. Notably, cell death was frequently evident within 2 hours or less of TDZD-8 exposure. Cellular and molecular studies indicate that the mechanism by which TDZD-8 induces cell death involves rapid loss of membrane integrity, depletion of free thiols, and inhibition of both the PKC and FLT3 signaling pathways [4].in vivo: Using mouse xenograft models, we demonstrated that LiCl and TDZD-8 significantly suppressed tumor development and growth of subcutaneous xenografts derived from human prostate cancer cells. Similarly, in the TRAMP mice, TDZD-8 and L803-mts reduced the incidence and tumor burden in the prostate lobes [2]. TDZD-8 significantly reduced the degree of pancreas injury, amylase, and lipase serum levels (p < .01); nuclear factor-kappaB activation (p < .01); the production of tumor necrosis factor-alpha and interleukin-1beta (p < .01); the expression of adhesion molecules and neutrophil accumulation (p < .01); the formation of oxygen and nitrogen-derived radicals (p < .01); the degree of lipid peroxidation (p < .01); the expression of transforming growth factor-beta and vascular endothelial growth factor (p < .01); and-ultimately-the mortality rate (p < .01) in rats [3].

SC-514 (GK 01140), a small molecule, is a selective inhibitor of IKK-2; does not inhibit other IKK isoforms or other serine-threonine and tyrosine kinases.IC50 Value: 11.2±4.7uM [1]Target: IKK2in vitro: IKK-2 inhibition by SC-514 is selective, reversible, and competitive with ATP. SC-514 inhibits transcription of NF-kappa B-dependent genes in IL-1 beta-induced rheumatoid arthritis-derived synovial fibroblasts in a dose-dependent manner [1]. Consistent with this observation, blocking IKKbeta kinase activity by SC-514 decreases the phosphorylation of p65/RelA at Ser-536 in the presence of Tax in human T-cell lymphotropic virus type I-transformed cells [2].in vivo: Co-treatment of mouse skin with the IKKbeta-specific inhibitorSC-514 (1 micromol) attenuated TPA-induced activation of Akt and NF-kappaB, and also the expression of COX-2 in hairless mouse skin [3].Clinical trial: No Development Reported

Resveratrol is one of the numerous polyphenolic compounds found in several vegetal sources, has a wide spectrum of targets with IC50 of 0.8, 1, 3.3 and 5 μM for Adenylyl cyclase, IKKβ, DNA polymerase α and δ, respectively.SU5416 is a potent and selective inhibitor of the VEGFR (Flk-1/KDR) that inhibits tyrosine kinase catalysis, and inhibits autophosphorylation of the Flk-1 receptor with an IC50 of 1.23±0.2 μM (n=4) using an ELISA-based biochemical kinase assay. SU-9516 is a selective CDK2 inhibtor with IC50 of 22 nM; less potent for CDK1/CDK4(IC50=40/200 nM), no inhibition on PKC, EGFR, p38MAPK etc.IC50 value: 22 nM/40 nM(CDK2/CDK1) [1]Target: CDK2 inhibitorin vitro: SU9516 is a potent inhibitor for cdk 2 and that it is 9-fold and 1.8-fold more selective for cdk2 than cdk4 and cdk1, respectively. Treatment with SU9516 (5 μM) inhibited (P ≤ 0.05) both cdk2-specific (27–64%) and cdk4-specific (26–49%) phosphorylation of pRb in SW480 cells at all (24, 48, and 72 h) time points. RKO cells remained blocked in G2-M at 20 h post-serum induction and -addition of SU9516. SU9516 produced a dose-dependent G1 accumulation in EGF-stimulated cells [1]. Treatment with 5 microM SU9516 prevented dissociation of pRb from E2F1 in all cell lines (HT-29>RKO>SW480). Treatment effects were time-dependent, demonstrating greater inhibition at 48 hr versus 24hr in HT-29 cells. Furthermore, E2F species were sequestered in complexes with p107, p130, DP-1, and cyclins A and E. After a 24-hr treatment with 5 microM SU9516, cyclin D1 and cdk2 levels decreased by 10-60% [2]. Exposure of U937 and other leukemia cells to SU9516 concentrations > or =5 microM rapidly (i.e., within 4 h) induced cytochrome c release, Bax mitochondrial translocation, and apoptosis in association with pronounced down-regulation of the antiapoptotic protein Mcl-1 [3].CGP 57380 is a cell-permeable pyrazolo-pyrimidine compound that acts as a selective inhibitor of Mnk1 with IC50 of 2.2 μM, but has no inhibitory activity against p38, JNK1, ERK1/2, PKC, or Src-like kinases.Piceatannol is a selective inhibitor of protein tyrosine kinase Syk. It could inhibit ICa,L, Ito, IKr, Ca2+ transients and Na+-Ca2+ exchange except IK1. Shows multiple biological activities such as anti-inflammatory, antiproliferative and immunomodulatory effects.In vitro: The treatment of human myeloid cells with piceatannol suppressed TNF-induced DNA binding activity of NF-κB. The effect of piceatannol was not restricted to myeloid cells, as TNF-induced NF-κB activation was also suppressed in lymphocyte and epithelial cells. Piceatannol also inhibited NF-κB activated by H2O2, PMA, LPS, okadaic acid, and ceramide. [1]IQ-1S (free acid) is an inhibitor of JNK kinases, with a preference for JNK3. Kd values for IQ-1S binding to JNK 1, 2 and 3 binding are 390, 360 and 87 nM, respectively. [1] Inhibits LPS-induced proinflammatory cytokine and nitric oxide production in vitro. Attenuates collagen-induced arthritis severity and inhibits murine delayed-type Doxycycline hypersensitivity in vivo. Anti-inflammatory and immunosuppressive.NU2058 is a guanine-based CDK inhibitor with IC50 of 17 μM and 26 μM for CDK2 and CDK1.IC50 value: 17μM (CDK2), 26μM (CDK1)Target: CDKin vitro: NU2058 is a competitive inhibitor of CDK2 with respect to ATP (Ki value CDK2, 12 3 μM) that binds in the ATP binding pocket in a different orientation from other purine-based inhibitors, including olomoucine and roscovotine. NU2058 is the lead compound in a structure-based drug discovery program to develop more potent and selective CDK inhibitors.

PHA-767491 (CAY10572) Hcl is a potent, ATP-competitive dual Cdc7/Cdk9 inhibitor with IC50 values of 10/34 nM. IC50 Value: 10 nM(Cdc7); 34 nM(Cdk9)Target: Cdc7/CDK9in vitro: PHA-767491 displays approximately 20-fold selectivity for Cdk1, Cdk2 and GSK3-β, 50-fold selectivity for MK2 and Cdk5 and 100-fold selectivity for PLK1 and CHK2. PHA-767491 inhibits cell proliferation in a variety of human cell lines with IC50 of 0.86 μM for SF-268 to 5.87 μM for K562, and significantly induces apoptosis in a p53-independent manner in almost all cell lines in contrast with 5-FU or gemcitabine which only works in a few of cell lines. Unlike current DNA synthesis inhibitors, PHA-767491 treatment at 5 μM blocks the initiation of DNA replication but not replication fork progression, due to specific inhibition of Cdc7 kinase and Mcm2 phosphorylation at the Cdc7-dependent Ser40 site. The direct mitochondrial dependent pro-apoptosis effect of PHA-767491 is also observed when applied at 1 μM in quiescent chronic lymphocytic leukemia (CLL) cells through the similar mechanism with EC50 of 0.34-0.97 μM. While in proliferating CLL cells stimulated by CD154 and interleukin-4, PHA-767491 treatment at 5 μM abolishes DNA synthesis by inhibiting Cdc7 rather than triggering cell death. The up-regulated Mcl-1 levels in ABT-737-resistant OCI-LY1 and SU-DHL-4 cells can be significantly decreased by PHA-767491 treatment at 3 μM possibly due to the inhibition of Cdk9, leading to the restoration of the sensitivity to ABT-737. in vivo: Administration of PHA-767491 twice a day for 5 days significantly inhibits the growth of HL60 xenograft in a dose-dependent manner with TGI of 50% and 92% at dose of 20 mg/kg and 30 mg/kg, respectively, the effect of which is also marked in A2780, Mx-1, and HCT-116 xenograft models as well as the DMBA-induced mammary carcinomas, and correlates with Cdc7 inhibition and subsequently decreased phosphorylation of Mcm2 at the Cdc7-dependent site Ser40.

kb NB 142-70 is a selective protein kinase D (PKD) inhibitor (IC50 values are 28.3, 58.7 and 53.2 nM for PKD1, 2 and 3 respectively).IC50 Value: 28.3 nM(PKD1); 58.7 nM(PKD2); 53.2 nM(PKD3)Target: PKDKb NB 142-70 inhibits prostate cancer cell migration and invasion and reduces wound healing in vitro. Kb NB 142-70 displays prominent cytotoxic and anti-proliferative effects.

BMS-345541 is a highly selective inhibitor of the catalytic subunits of IKK-2 and IKK-1 with IC50 of 0.3 μM and 4 μM, respectively.IC50 value: 0.3/4 uM(IKK2/1) [1]Target: IKK2/1in vitro: BMS-345541 dose-dependently inhibits the TNF-α-stimulated phosphorylation of IκBα in THP-1 monocytic cells with an IC50 of ~4 μM. BMS-345541 inhibits lipopolysaccharide-stimulated tumor necrosis factorα, interleukin-1β, interleukin-8, and interleukin-6 in THP-1 cells with IC50 values in the 1- to 5 μM range. BMS-345541 binds in a mutually exclusive manner with respect to a peptide inhibitor corresponding to amino acids 26 - 42 of IκBα with Ser-32 and Ser-36 changed to aspartates and in a non-mutually exclusive manner with respect to ADP. BMS-345541 binds to similar allosteric sites on IKK-1 and IKK-2, which then affects the active sites of the subunits differently [1]. BMS-345541 (10 μM) inhibits growth of Normal human epidermal melanocytes, and metastatic melanoma cells (SK-MEL-5, A375, and Hs 294T) by 96% and 99% at 72h, respectively. Application of 100 μM of BMS-345541 to SK-MEL-5 cell culture results in 87% apoptotic cells at 24 h through caspase-independent and AIF-dependent mitochondria-mediated manner. BMS-345541 treatment (10 μM) results in 76% and 95% reduction in IKK activities and NF-kB activity, as well as CXCL1 production [2]. BMS-345541 inhibits the TNFα-induced expression of both ICAM-1 and VCAM-1 in human umbilical vein endothelial cells with IC50 of 5 μM [3].in vivo: BMS-345541 effectively inhibits melanoma tumor growth in a dose-dependent manner. Tumor-bearing mice treated with 75 mg/kg of BMS-345541 shows effective inhibition of growth of SK-MEL-5, A375, and Hs 294T tumors by 86 %, 69% and 67%, respectively, when compared with control animals treated with vehicle alone [2].

Bakuchiol is a phytoestrogen isolated from the seeds of Psoralea corylifolia L; has anti-tumor effects.IC50 value:Target:in vitro: Bakuchiol reduced mitochondrial membrane potential (Psim) of cells in a concentration- and time-dependent manner, showing a more potent effect than that of resveratrol. S phase arrest, caspase 9/3 activaton, p53 and Bax up-regulation, as well as Bcl-2 down-regulation were observed in bakuchiol-treated A549 cells [1]. UGT2B7 was inhibited by the strongest intensity. The noncompetitive inhibition was demonstrated by the results obtained from Dixon plot and Lineweaver-Burk plot. The Ki value was calculated to be 10.7 μM [2]. Bakuchiol was found to be naturally occurring potent inhibitors of hCE2, with low Ki values ranging from 0.62μM to 3.89μM [3]. After exposure to bakuchiol at 0.25-fold, 0.5-fold and 1-fold of minimum inhibitory concentration (MIC) (3.91 μg/ml) for 24h, the fungal conidia of T. mentagrophytes demonstrated a significant dose-dependent increase in membrane permeability. Moreover, bakuchiol at 1-fold MIC elicited a 187% elevation in reactive oxygen species (ROS) level in fungal cells after a 3-h incubation [4].in vivo: In combination with the reported concentration after an intravenous administration of bakuchiol (15 mg/kg) in rats, the high risk of in vivo inhibition of bakuchiol towards UGT2B7-catalyzed metabolism of drugs was indicated [2]. In a guinea pig model of tinea pedis, bakuchiol at 1%, 5% or 10% (w/w) concentration in aqueous cream could significantly reduce the fungal burden of infected feet (p<0.01-0.05) [4].

Necrostatin-1 is a specific inhibitor of the receptor-interacting protein 1 (RIP1) kinase domain, inhibits necroptosis with EC50 of 490 nM in Jurkat cells.

Anisomycin is a pyrrolidine antibiotic, acts as an anti-fungal antibiotic which inhibits Protein Synthesis, also is a potent activator of SAPKs/JNKs.Target: antibioticin vitro: Anisomycin inhibits EAC cell proliferation in concentration-dependent manner. [2] Anisomycin (3 μM) decreases protein synthesis in MDA16 and MDA-MB-468 cells, and reduces colony formation by MDA-MB-468 cells. Anisomycin causes an increase in the number of apoptotic cells in MDA-MB-468 cultures, but not in MDA16 cultures. Anisomycin actives JNK phosphorylation in MDA-MB-468 cells.[3] in vivo: Peritumoral administration of anisomycin (5 mg/kg) significantly suppresses Ehrlich ascites carcinoma (EAC) growth resulting in the survival of approximately 60% of the mice 90 days after EAC inoculation. [2]

Formononetin (Formononetol; Flavosil) is a bioactive component extracted from the red clover; inhibits the proliferation of DU-145/PC-3 cells in a dose-dependent manner.IC50 value:Target: anti-cancer in vitro: formononetin inhibited the proliferation of DU-145 cells in a dose-dependent manner. DU-145 cells treated with different concentrations of formononetin displayed obvious morphological changes of apoptosis under fluorescence microscopy. In addition, formononetin increased the proportion of early apoptotic DU-145 cells, down-regulated the protein levels of Bcl-2 and up-regulated those of RASD1 and Bax [1]. Formononetin significantly inhibited the cell growth of PC-3 in a dose-dependent manner, but no such effect was observed in RWPE1 cells. Formononetin treatment contributed to the reduced Bcl-2 protein level and the elevated Bax expression in PC-3 cells, thereby resulting in the increasing Bax/Bcl-2 ratios. Furthermore, the phosphorylated level of p38 in PC-3 cells was activated through the FN treatment, whereas the endogenous Akt phosphorylation was blocked [2]. Compared with the control, formononetin inhibited the proliferation of MCF-7 cells and effectively induced cell cycle arrest. The levels of p-IGF-1 R, p-Akt, cyclin D1 protein expression, and cyclin D1 mRNA expression were also downregulated [3].in vivo: formononetin also prevented the tumor growth of human breast cancer cells in nude mouse xenografts [3].

Apigenin is a non-toxic and non-mutagenic flavone that exists abundantly in numerous herbs and vegetables.IC50 value:Target:In vitro: Apigenin reduced viability and migratory properties, increased apoptosis, and suppressed mitochondrial membrane potential in both the JAR and JEG3 cells. In addition, apigenin predominantly decreased phosphorylation of AKT, P70RSK and S6 whereas the phosphorylation of ERK1/2 and P90RSK was increased by apigenin treatment of JAR and JEG3 cells in a dose-dependent manner. Moreover, treatment of JAR and JEG3 cells with both apigenin and pharmacological inhibitors of PI3K/AKT (LY294002) and ERK1/2 (U0126) revealed synergistic anti-proliferative effects [1].In vivo:Using NF-κB luciferase transgenic mice, we found that apigenineffectively modulated NF-κB activity in the lungs, suggesting the ability of dietary compounds to exert immune-regulatory activity in an organ-specific manner [2]. In rabbit articular chondrocytes, apigenin inhibited the gene expression of MMP-3, MMP-1, MMP-13, ADAMTS-4, and ADAMTS-5. Furthermore, apigenin inhibited production of MMP-3 protein in vivo [3].Genistein is a potent inhibitor of the protein tyrosine kinase (PTK) activity of the EGFR in vitro with an IC50 of 0.7 μg/mL (0.6 μM).

SAR245409 (XL765) is a potent and highly selective paninhibitor of class I PI3Ks (α/β/γ/δ, IC50=39/110/9/43 nM) with activity against mTOR(IC50=160-910 nM).IC50 value: 9 nM (p110γ); 39/110/9/43 nM(α/β/γ/δ) [1][4]Target: mTOR/PI3Kin vitro: XL765 is active against class I PI3K (IC50 = 39, 113, 9 and 43 nM for p110α, β, γ and δ, respectively). XL765 also inhibits DNA-PK (IC50 = 150 nM) and mTOR (IC50 = 157 nM) but not XL-147 which shows IC50 values of > 15 μM [1]. XL765 treatment results in decreased cell viability in 13 PDA cell lines in a dose-dependent manner. XL765, a dual-target PI3K/mTOR inhibitor, inhibits cell growth and apoptosis in many more cell lines and at lower concentrations as compared to the PI3K-selective inhibitors XL147 and PIK90. The effect can be recapitulated by using combinations of single-targeted compounds. XL765 significantly reduces phosphorylation of the mTOR targets S6, S6K, and 4EBP1, which is associated with greater apoptosis induction rather than to PI3K inhibition alone. XL765 treatment causes accumulation of autophagosomes in MIAPaCa-2 cells, and results in significant dose-dependent AVO induction and LC3-II stimulation in MIAPaCa-2 cells stably expressing a LC3-GFP construct [2].in vivo: The combination of XL765 (30 mg/kg) with chloroquine (50 mg/kg) results in significant inhibition of BxPC-3 xenograft growth in mice models, while XL765 alone at the same dose has no inhibitory effect [2]. Oral administration of XL765 results in greater than 12-fold reduction in median tumor bioluminescence compared to control and improvement in median survival in nude mice implanted intracranially with GBM 39-luc cells. XL765 in combination with temozolomide (TMZ) yields a 140-fold reduction in median bioluminescence with a trend toward improvement in median survival compared with TMZ alone [3].

Butein, a plant polyphenol isolated from Rhus verniciflua, inhibit the activation of protein tyrosine kinase and EGFR. target: EGFR [1]In vitro: 1) Butein inhibited the activation of AKT, extracellular signal-regulated kinase (ERKs) and p38 kinases in the presence of cisplatin.[2] 2) FoxO3a and its downstream molecules play a role in the synergistic effects of butein and cisplatin.[2]3) Butein suppresses cell proliferation and enhances apoptosis in paclitaxel-resistant ovarian cancer cells.[3]4) Butein activates FOXO3a/p27kip1 pathway in ALL cell lines.[4]5) Butein inhibited not only the epidermal growth factor (EGF)-stimulated auto-phosphotyrosine level of EGF receptor in HepG2 cells but also tyrosine-specific protein kinase activities of EGF receptor (IC50= 65 μM) and p60c-src(IC50= 65 μM)In vivo: 1) Butein in combination with cisplatin suppresses tumor growth and increases FoxO3a expression.[1]

Bikinin(Abrasin) is a potent inhibitor of plant GSK-3/Shaggy-like kinase; activates BR signaling downstream of the BR receptor..IC50 value:Target: GSK-3/Shaggy-like kinase inhibitorin vitro: Bikinin is a potent inhibitor of group I and group II ASKs. ASKθ, a group III ASK is moderately inhibited. The second kinase of this class, ASKβ, and the group IV kinase ASKδ are not inhibited. plants treated with the ASK inhibitor bikinin show the typical signs of constitutive BR response including elongated hypocotyls and light-green leaves indicating that most or all ASKs crucial for BR signalling are inhibited [1]. Bikinin directly binds the GSK3 BIN2 and acts as an ATP competitor. Furthermore, bikinin inhibits the activity of six other Arabidopsis GSK3s [3].in vivo: Bikinin, a GSK3 kinase inhibitor, inhibited the SnRK2.3 kinase activity and its T180 phosphorylation in vivo [2].

RG14620 is an epidermal growth factor receptor (EGFR) inhibitor, with IC50 values of 3 μM for HER 14 colony formation and 1 pM for HER 14 DNA synthesis.

TC-DAPK 6 is a potent, ATP-competitive, and highly selective DAPK inhibitor (IC50=69 and 225 nM against DAPK1 and DAPK3, respectively, with 10 μM ATP).

TPCA-1 is a potent inhibitor of IKK-2 with IC50 of 17.9 nM.

BX517 is a potent and selective inhibitor of PDK1 with IC50 of 6 nM.

Dihydroartemisinin, one of the most active artemisinin derivative, exhibits anticancer activity in a number of human cancer cells.Scutellarin, a main active ingredient extracted from Erigeron breviscapus (Vant.) Hand-Mazz., has been wildly used to treat acute cerebral infarction and paralysis induced by cerebrovascular diseases.

BMS-345541 is a highly selective inhibitor of the catalytic subunits of IKK-2 and IKK-1 with IC50 of 0.3 μM and 4 μM, respectively.

AG-490 is an tyrosine kinase inhibitor, inhibits EGFR and Stat-3.[6]-Gingerol is an active compound isolated from Ginger (Zingiber officinale Rosc), exhibits a variety of biological activities including anticancer, anti-inflammation, and anti-oxidation.

Poloxin is a non-ATP competitive Polo-like Kinase 1 (PLK1) inhibitor that targets the polo-box domain.

AmLexanox is a specific inhibitor of IKKε and TBK1, and inhibits the IKKε and TBK1 activity determined by MBP phosphorylation with an IC50 of approximately 1-2 μM.

Quercetin, a natural flavonoid, is a stimulator of recombinant SIRT1 and also a PI3K inhibitor with IC50 of 2.4-5.4 μM.

NSC23005 sodium is a novel and effective p18 inhibitor (ED50=5.21 nM) in promoting Hematopoietic stem cells (HSCs) expansion in both murine and human models.IRAK inhibitor 2 is interleukin-1 receptor associated kinase inhibitor .

AR-A014418 is a selective and effective GSK3β inhibitor with an IC50 value of 104 nM, and has no significant inhibition on 26 other kinases.

TCS-PIM-1-4a is a Pim inhibitor that blocks mTORC1 activity via activation of AMPK; kills a wide range of both myeloid and lymphoid cell lines (with IC50 values ranging from 0.8 to 40 μM).IC50 value:Target: Pim SMI-4a a novel benzylidene-thiazolidine-2, 4-dione small molecule inhibitor of the Pim kinases, kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre-T-LBL/T-ALL) being highly sensitive. Incubation of pre-T-LBL cells with SMI-4a induced G1 phase cell-cycle arrest secondary to a dose-dependent induction of p27(Kip1), apoptosis through the mitochondrial pathway, and inhibition of the mammalian target of rapamycin C1 (mTORC1) pathway based on decreases in phospho-p70 S6K and phospho-4E-BP1, 2 substrates of this enzyme. In addition, treatment of these cells with SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2), and the combination of SMI-4a and a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor was highly synergistic in killing pre-T-LBL cells. SMI-4a blocked the rapamycin-sensitive mTORC1 activity by stimulating the phosphorylation and thus activating the mTORC1 negative regulator AMP-dependent protein kinase (AMPK).

GW 441756 is a specific Tropomyosin-related kinase A (TrkA) inhibitor with an IC50 value of 2 nM; little activity to c-Raf1 and CDK2.IC50 Value: 2 nM [1]Target: TrkAin vitro: GW441756 specifically blocked TrkA-induced cell death in a dose-dependent manner, but there was no effect in uninduced cells. TrkA ability to induce γH2AX production was significantly downregulated by both K-252a and GW441756 in the absence of DNA damage inducer. In addition, it was also suppressed by K-252a during DNA damage by doxorubicin treatment, but not by GW441756 [2].

SC66 is a novel AKT inhibitor, IC50 values of approximately 0.75 μg/ml at 72 hours in HepG2, HA22T/VGH and PLC/PRF/5 cells.IC50 value: 0.75 μg/ml (72 hours in HepG2, HA22T/VGH and PLC/PRF/5 cells) [1]Target: Aktin vitro: Each cell line had a different sensitivity to SC66, as evidenced by the IC50 values . HepG2, HA22T/VGH and PLC/PRF/5 cells had similar IC50 values of approximately 0.85 and 0.75 μg/ml at 48 and 72 hours, respectively. The most resistant cell line was Huh7, which showed an IC50 of 3.1 and 2.8 μg/ml at 48 and 72 hours respectively, while the Hep3B cell line was found to be the most sensitive, with an IC50 of 0.75 and 0.5 μg/ml at 48 and 72 hours, respectively. SC66 reducew cell viability in a dose- and time-dependent manner, inhibited colony formation and induced apoptosis in HCC cells. SC66 treatment led to a reduction in total and phospho-AKT levels. In addition, SC66 induces the production of reactive oxygen species (ROS) and DNA damage. SC66 significantly potentiates the effects of both conventional chemotherapeutic and targeted agents, doxorubicin and everolimus, respectively. [1] SC66 manifests a more effective growth suppression of transformed cells compared with other inhibitors of PIP3/Akt pathway. SC66 represents a unique chemical tool to investigate the mechanisms of ubiquitination-dependent Akt regulation in physiological and stressed conditions. SC66 directly facilitates Akt ubiquitination. [2]In vivo: SC66 inhibits tumor growth of Hep3B cells in xenograft models. [1]

Indirubin-3'-monoxime is a powerful inhibitor of GSK-3β with IC50 of 22nM, also inhibits CDK1/5 (IC50 = 180/100 nM).IC50 value: 22 nM [1]Target: GSK-3βin vitro: Indirubin-3′-monoxime acts as a competitive inhibitor of ATP binding. The apparent Ki was 0.85 μM. [1] In cell-based and cell-free assays, Indirubin-3'-monoxime selectively inhibits 5-lipoxygenase (5-LO), the key enzyme in LT biosynthesis, with an IC50 in the low micromolar range. Indirubin-3'-monoxime causes a concentration-dependent inhibition of all analysed products formed via the 5-LO pathway independent of the stimulus with IC50 values of 4.1 ± 1.1 and 4.3 ± 1.1 μM. [2]in vivo: Indirubin-3′-monoxime also inhibits the phosphorylation of DARPP-32 by CDK5 on Thr-75, thereby mimicking one of the effects of dopamine in the striatum.[1] Indirubin-3'-monoxime is a potent inhibitor of vascular smooth muscle cell (VSMC) proliferation (IC50 2 μM) and successfully blocks neointima formation in a murine femoral cuff model. [2] Indirubin-3′-monoxime is a GSK3β inhibitor, attenuates the HFD induced cognitive impairment in mice.Indirubin-3′-monoxime augment the level of brain insulin and BDNF in high fat diet fed mice. [3]

Compound 401 is a synthetic inhibitor of DNA-PK (IC50 = 0.28 μM) that also targets mTOR but not PI3K.IC50 value: 0.28 μM [1]Target: DNA-PKin vitro: Compound 401 shows activity against mTOR (IC50 = 5.3 μM) but not p110α/p85α PI3K (IC50 > 100 μM). Treatment of cells with Compound 401 blocks the phosphorylation of sites modified by mTOR-Raptor and mTOR-Rictor complexes (ribosomal protein S6 kinase 1 Thr389 and Akt Ser473, respectively). [1]PP1 is a potent, and Src family-selective tyrosine kinase inhibitor with IC50 of 5 and 6 nM for Lck and Fyn, respectively.Tyrphostin A9(AG 17), a tyrosine kinase inhibitor, is a potent inducer of mitochondrial fission. Tyrphostin A9 emerged as the most potent and selective of 51 tyrosine kinase inhibitors tested against the TNF-induced respiratory burst. IC50 value: Target: Multi tyrosine kinaseTyrphostin A9 inhibited TNF-induced tyrosine phosphorylation of pyk2 without blocking the cells' bactericidal activity. Tyrphostin A9 is a PDGF receptor tyrosine kinase inhibitor (IC50 = 500 nM). Recent findings suggest that signaling via PDGF receptor tyrosine kinases is not necessary for the shift of the smooth muscle cells from a contractile to a synthetic phenotype. On the other hand these enzymes apparently carry out important functions in the control of intracellular membrane traffic and cell division.

Y15 is a direct and specific inhibitor of FAK auto-phosphorylation.

Wogonin is a cell-permeable and orally available flavonoid that displays anti-inflammatory and anticancer properties. IC50 value: Target: in vitro: wogonin induced a G1 phase cell cycle arrest in HCT116 cells in a concentration- and time-dependent manner. Meanwhile, the cell cycle-related proteins, such as cyclin A, E, D1, and CDK2, 4 were down-regulated in wogonin-induced G1 cell cycle arrest. Furthermore, we showed that the anti-proliferation and G1 arrest effect of wogonin on HCT116 cells was associated with deregulation of Wnt/β-catenin signaling pathway [1]. Wogonin could potently promote Aβ clearance in the primary neural astrocytes and significantly decrease Aβ secretion in SH-SY5Y-APP and BACE1 cells through the mTOR/autophagy signaling pathway [2]. wogonin not only inhibited the expression and interaction of TLR4, MyD88, and TAK1, but also reduced the activation of nuclear factor kappa B and mitogen-activated protein kinases pathway in LPS-treated DRG neurons. Moreover, wogonin significantly suppressed the release of pro-inflammatory mediators in LPS-induced DRG neurons, including cyclooxygenase-2, inducible nitric oxide synthases, interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha [3]. Wogonin up-regulated transcription factor GATA-1 and enhanced binding between GATA-1 and FOG-1, thereby increasing expression of erythroid-differentiation genes. Wogonin also up-regulated the expression of p21 and induced cell cycle arrest [5].in vivo: Treatment with Wogonin reduced CLP-induced release of HMGB1 and sepsis-related mortality and pulmonary injury in mice [4]. In vivo results indicated that wogonin attenuated LPS-induced histological alterations. Peripheral blood leucocytes decreased in the LPS-induced group, which was ameliorated by wogonin. In addition, wogonin inhibited the production of several inflammatory cytokines, including tumour necrosis factor-α, interleukin-1β (IL-1β) and IL-6 [6].

Zoledronic acid monohydrate(CGP 42446; ZOL 446) is an activator of protein kinase C with apoptotic effects on multiple myeloma cell lines. It inhibited proliferation of human foetal osteoblastic cell line (hFOB) with an IC50 of 40 uM.Target: PKCZoledronic acid at doses of 2.0 and 4.0 mg and pamidronate at a dose of 90 mg each significantly reduced the need for radiation therapy to bone (P < 0.05) in contrast with 0.4 mg zoledronic acid, which did not. Skeletal-related events of any kind, pathologic fractures, and hypercalcemia also occurred less frequently in patients treated with 2.0 or 4.0 mg zoledronic acid or pamidronate than with 0.4 mg zoledronic acid [1]. Zoledronic acid administration may be a potentially valuable adjunct to distraction osteogenesis treatment, to enhance bone strength, thus reducing refracture complications [2]. Zoledronic acid, a more recent drug, was compared with pamidronic acid in two clinical trials, but the results are unconvincing because of the unusually poor performance of pamidronic acid. Safety of zoledronic acid is uncertain, owing to a lack of long-term data [3].Clinical indications: Bone metastases; Breast tumor; Complex regional pain syndrome; Hypercalcemia; Lower back pain; Male osteoporosis; Mesothelioma; Metastasis; Metastatic breast cancer; Multiple myeloma; Osteoarthritis; Osteogenesis imperfectaFDA Approved Date: 2007Toxicity: Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia.

CHR-6494 is a potent and selective Haspin (Haploid Germ Cell-Specific Nuclear Protein Kinase) inhibitor that blocks H3T3ph phosphorylation. IC50 Value: N/ATarget: Haspin KinaseCHR-6494 is a first-in-class Haspin inhibitor with a wide spectrum of anticancer effects. Recent research showed that CHR-6494 reduces H3T3ph levels in a dose-dependent manner and causes a mitotic catastrophe characterized by metaphase misalignment, spindle abnormalities and centrosome amplification. From the cellular standpoint, the identified small-molecule Haspin inhibitor causes arrest in G2/M and subsequently apoptosis. Importantly, ex vivo assays also demonstrate its anti-angiogenetic features; in vivo, it shows antitumor potential in xenografted nude mice without any observed toxicity.

IRAK inhibitor 1 is a potent IRAK-4 inhibitor with IC50 of 216 nM, is poorly active against JNK-1 and JNK-2 with IC50 of 3.801 μM, and >10 μM, respectively.

SU 5402 is a potent multi-targeted receptor tyrosine kinase inhibitor with IC50 of 20 nM, 30 nM, and 510 nM for VEGFR2, FGFR1, and PDGFRβ, respectively.SKF-86002 is a potent inhibitor of p38 MAP kinase wit IC50 of 0.5-1 uM; inhibits LPS-induced IL-1 and TNF-α production in human monocytes (IC50 = 1 μM).IC50 value:Target: p38 MAPK inhibitorin vitro: SKF-86002 inhibited prostaglandin H2 (PGH2) synthase activity (IC50 120 microM) as well as prostanoid production by rat basophilic leukemia (RBL-1) cells (IC50 70 microM) and its sonicate (IC50 100 microM) and human monocytes (IC50 1 microM). In addition, SK&F 86002 inhibited the generation of dihydroxyeicosatetraenoic acid (diHETE) and 5-hydroxyeicosatetraenoic acid (5-HETE) by a high speed supernatant fraction of RBL-1 cells (IC50 10 microM) [1]. differentiation of HL-60 cells toward the neutrophil phenotype resulted in a loss in c-Jun NH2-terminal kinase activation with concomitant acquisition of formylmethionylleucylphenylalanine-stimulatable and stress-inducible p38 MAPK activity as well as apoptosis blockade by SKF-86002 [2]. SKF-86002 blocked superoxide anion production in response to FMLP and reduced adhesion and chemotaxis in response to PAF or FMLP [3].

ID-8 is a DYRK inhibitor, and sustains embryonic stem cell self-renewal in long-term culture.IC50 Value: Target: DYRKin vitro: the combination of Wnt and ID-8 enhanced hESC replating efficiency, and colonies expressed ALP and displayed undifferentiated morphology. members of the DYRK family are direct targets of ID-8 and that ID-8 enhances Wnt-mediated hESC survival and proliferation via inhibition of DYRKs [1]. ID-8 stimulated proliferation at a steady rate similar to LIF. ID-8 is required to maintain nanog, Sox2, and Rex-1 gene expression [2]. In vivo: Nocodazole is a rapidly-reversible inhibitor of microtubule polymerization, which exhibits good potency against ABL, ABL(E255K), and ABL(T315I) with IC50 values of 0.21 μM, 0.53 μM, and 0.64 μM, respectively, and increases CRISPR/Cas9-mediated editing frequencies.PP2 is a potent, reversible, ATP-competitive, and selective inhibitor of the Src family of protein tyrosine kinases with IC50s of 4 and 5 nM for Lck and Fyn, respectively. SKI-II is a synthetic inhibitor of sphingosine kinase (SK) activity with IC50 of 78 μM for SK1 and 45 μM for SK2.IC50 value: 78/45 μM (SK1/2) [2]Target: SKin vitro: SKI II inhibits cell proliferation by suppressing the Wnt/β-catenin signaling pathway. SKI II also reduces the expression of c-Myc and cyclin D1, the downstream target genes of the Wnt signaling pathway. SKI II inhibits cell proliferation by suppressing the Wnt/β-catenin signaling pathway. SKI II promotes the degradation of β-catenin by enhancing Wnt5A. SKI II inhibits the proliferation of HepG2 cells by blocking the Wnt/β-catenin signaling pathway. [1]in vivo: SKI-II causes an irreversible inhibition of SK1 by inducing its lysosomal and/or proteasomal degradation. In the present study, SKI-II was administered 3-weekly i.p. to LDL-R-/- mice for 16 weeks at a dose previously demonstrated to reduce tumor growth in mice. Preliminary experiments revealed that a single administration of SKI-II produces a significant reduction of plasma S1P with the maximum (40%) observed 12 h after injection. [2]

MCB-613 is a potent, pan steroid receptor coactivator (SRC) stimulator.Target: SRCin vitro: MCB-613 exerts the greatest activation of SRC-1 in the primary screen, is confirmed to be a strong activator of all three SRCs. MCB-613 can super-stimulate SRCs' transcriptional activity. MCB-613 increases SRCs' interactions with other coactivators and markedly induces ER stress coupled to the generation of reactive oxygen species (ROS). MCB-613 selectively and reversibly binds to the RID of SRC-3, and selectively kills cancer cells including MCF-7 (breast), PC-3 (prostate), H1299 (lung), and HepG2 (liver) cells, without toxicity to mouse primary hepatocytes and mouse embryonic fibroblasts (MEFs). MCB-613 also increases SRCs' interactions with other coactivators and markedly induces ER stress coupled to the generation of reactive oxygen species (ROS). [1]in vivo: In an MCF-7 breast cancer mouse xenograft model, MCB-613 (20 mg/kg, i.p.) significantly and dramatically inhibits the growth of the tumor while causing no obvious animal toxicity and body weight less. [1]

AG-1024 (Tyrphostin) inhibits IGF-1R autophosphorylation with IC50 of 7 μM, less potent to IR with IC50 of 57 μM.IC50 value: 7 uM (IGF-1R autophosphorylation); 57 uM (IR) [1]Target: IGF-1R; IRin vitro: AG-1024 blocks the IGF-1 receptor and IR autophosphorylation with IC50 of 7 μM and 57 μM, respectively. AG-1024 also inhibits the receptor tyrosine kinase activity towards exogenous substrates (TKA) with IC50 values of 18 μM and 80 μM, respectively [1]. Human breast cancer cell line MCF-7 exposure to Tyrphostin AG 1024 inhibited proliferation and induced apoptosis in a time-dependent manner, and the degree of growth inhibition for IC20 plus irradiation (4 Gy) was up to 50% compared to the control. Examination of Tyrphostin AG 1024 effects on radiation response demonstrated a marked enhancement in radiosensitivity and amplification of radiation-induced apoptosis [2]. AG-1024 significantly inhibits melanoma cell proliferation with an IC50 of <50 nM in the absence of serum, by blocking MAPK/ERK2 signaling, subsequently rapidly inducing pRb dephosphorylation and activation, and eventually the formation of growth suppressive pRb-E2F complexes [3].in vivo: Administration of AG-1024 at a dose of 30 μg for 10 days significantly inhibits the tumor growth of Ba/F3-p210 xenograft in mice [4].

AS-252424 is a potent and selective inhibitor of PI3Kγ with IC50 of 33 nM; >10 fold selectivity for PI3Kγ versus PI3Kα.IC50 value: 33±10 nM [1]Target: PI3Kγ inhibitorin vitro: Compound 26 (AS-252424), a potent and selective small-molecule PI3Kγ inhibitor emerging from these efforts, was further profiled in three different cellular PI3K assays and shown to be selective for class IB PI3K-mediated cellular effects [1]. ZSTK474 and AS252424 reduced ET(A) receptor-evoked TRPC1/C5/C6 channel activity but potentiated TRPC3/C7 channel activity [2]. The pharmacological inhibition of PI3Kγ (phosphatidylinositol 3-kinase) with AS252424, concentration-dependently reduced T24 cell proliferation induced by BK or des-Arg(9)-BK [3].in vivo: Oral administration of 26(AS-252424) in a mouse model of acute peritonitis ledto a significant reduction of leukocyte [1]. recruitment.LY294002 is a broad-spectrum inhibitor of PI3K, with IC50 of 0.5/0.57/0.97 μM for PI3Kα/δ/β, respectively, also potently inhibits CK2 with IC50 of 98 nM.

Hydroxyfasudil(HA1100), metabolite of Fasudil, is a potent Rho-kinase inhibitor and vasodilator.IC50 Value: 0.12 uM (ROCK1); 0.17 uM (ROCK2) [1]Target: ROCKin vitro: Fasudil (1-10 μM) and hydroxyfasudil (0.3-10 μM) significantly prevented endothelin-induced cardiomyocyte hypertrophy [2]. Hydroxyfasudil significantly attenuated serotonin (IC)-induced vasoconstriction of SA (-7 +/- 1% vs. 2 +/- 1%, p < 0.01). Coronary I/R significantly impaired coronary vasodilation to acetylcholine after I/R (SA, p < 0.05; and A, p < 0.01 vs. before I/R) and L-NMMA further reduced the vasodilation, whereas hydroxyfasudil completely preserved the responses.in vivo: Treatment with hydroxyfasudil significantly improved bladder intercontraction intervals. Rats treated with hydroxyfasudil also showed a significant reduction of histopathological features associated with cystitis [3]. Twelve-week-old male SHRs were treated with hydroxyfasudil (3 or 10 mg/kg, i.p.) once a day for 6 weeks. Treatment with hydroxyfasudil significantly improved the decreased penile cGMP concentrations, the increased Rho kinase activities, the increased norepinephrine-induced contractions, and the decreased acetylcholine-induced relaxation in a dose-dependent manner [4]. Toxicity: The proportion of patients with good clinical outcome was 74.5% (41/55) in the fasudil group and 61.7% (37/60) in the nimodipine group. There were no serious adverse events reported in the fasudil group [5]. Clinical trial: N/A

LY3177833 is an CDC7 and pMCM2 inhibitor extracted from patent US 20140275131and patent WO 2014143601 A1 compound example 4; has IC50 values of 3.3 nM and 290 nM, respectively.INK-128 is a potent and selective mTOR inhibitor with IC50 of 1 nM, > 200-fold less potent to class I PI3K isoforms, superior in blocking mTORC1/2 and sensitive to pro-invasion genes.TSU-68 is a novel multiple receptor tyrosine kinase inhibitor with IC50 of 2.1 μM, 8 nM and 1.2 μM for VEGF-R1, PDGF-Rβ and FGF-R1, respectively, and has greatest potency against PDGFR autophosphorylation.IC261 is a novel inhibitor of CK1, triggers the mitotic checkpoint control. The IC50 of IC261 for CK1 was 16 μM and for Cdk5 is 4.5 mM. IC50 value: 16 μM [2]Target: CK1in vitro: IC261 is a specific inhibitor of the protein kinases casein kinase 1-delta and -epsilon, triggers the mitotic checkpoint and induces p53-dependent postmitotic effects. At low micromolar concentrations IC261 inhibits cytokinesis causing a transient mitotic arrest. IC261 selectively inhibits CK1 compared to other protein kinases by an ATP-competitive mechanism. [1]

Thiazovivin (Tzv) is a novel ROCK inhibitor with IC50 of 0.5 μM, promotes hESC survival after single-cell dissociation.IC50 Value: 0.5 μMTarget: ROCKin vitro: Thiazovivin treatment significantly enhances the survival of human embryonic stem cells (hESCs) after enzymatic dissociation more than 30-fold, while homogenously maintaining pluripotency with the characteristic colony morphology, expression of typical pluripotency markers such as alkaline phosphatase (ALP), and normal karyotype. Dissociated hESCs treated with Thiazovivin display dramatically increased adhesion to matrigel- or laminin-coated plates but not to gelatin-coated plates within a few hours. Thiazovivin treatment increases cell-ECM adhesion-mediated β1 integrin activity, which synergizes with growth factors to promote cell survival. In addition to activating integrin, Thiazovivin but not Tyrintegin (Ptn) protects hESCs from death in the absence of ECM in suspension through E-cadherin-mediated cell-cell interaction. Thiazovivin treatment potently inhibits endocytosis of E-cadherin, consequently stabilizing E-cadherin on the cell surface and leading to reestablishment of cell-cell interaction, which is essential for hESC survival in ECM-free conditions. Thiazovivin but not Tyrintegin (Ptn) at 2 μM inhibits Rho-associated kinase (ROCK) activity and protects hESCs at a similar level as the widely used selective ROCK inhibitor Y-27632 at 10 μM, suggesting that Rho-ROCK signaling regulates cell-ECM and cell-cell adhesion. Thiazovivin at 1 μM increases the reprogramming efficiency of CB mononuclear cells to induced pluripotent stem cells (iPSCs) by more than 10 times. in vivo: N/A

Isorhamnetin is an O-methylated flavonol, a flavonoid aglucon.

Vps34-PIK-III is a potent and selective inhibitor of VPS34 with an IC50 of 18 nM.Y-27632 dihydrochloride is an ATP-competitive inhibitor of ROCK-I and ROCK-II, with Ki of 220 nM and 300 nM for ROCK-I and ROCK-II, respectively.Triciribine is a DNA synthesis inhibitor, also inhibits Akt and HIV-1/2 with IC50 of 130 nM, and 0.02-0.46 μM, respectively.

RKI-1447 is a potent small molecule inhibitor of ROCK1 and ROCK2 with IC50 values of 14.5 nM and 6.2 nM, respectively.

GSK1059615 is a dual inhibitor of PI3Kα/β/δ/γ (reversible) and mTOR with IC50 of 0.4 nM/0.6 nM/2 nM/5 nM and 12 nM, respectively.

LM22A-4 is a specific agonist of tyrosine kinase receptor B, used for neurological disease research.Pim1/AKK1-IN-1 is a potent multi-kinase inhibitor with Kd values of 35 nM/53 nM/75 nM/380 nM for Pim1/AKK1/MST2/LKB1 respectively, and also inhibits MPSK1 and TNIK.

PRT-060318 (PRT318) is a novel selective inhibitor of the tyrosine kinase Syk with an IC50 of 4 nM.MSC2530818 is a potent, selective and orally available CDK8/19 inhibitor with an IC50 of 2.6 nM for CDK8.

AT13148 is an orally active and ATP-competitive, multi-AGC kinase inhibitor with IC50s of 38 nM/402 nM/50 nM, 8 nM, 3 nM, and 6 nM/4 nM for Akt1/2/3, p70S6K, PKA, and ROCKI/II, respectively. STO-609 is a selective and cell-permeable inhibitor of the Ca2+/calmodulin-dependent protein kinase kinase (CaM-KK), with Ki values of 80 and 15 ng/mL for recombinant CaM-KKα and CaM-KKβ, respectively.AG-1478 is a selective EGFR tyrosine kinase inhibitor with IC50 of 3 nM.TyrphostinAG879 is a tyrosine kinase inhibitor that inhibits TrKA phosphorylation, but not TrKB and TrKC.[1] also a ErbB2 kinase inhibitor, has at least 500-fold higher selectivity to ErbB2 (IC50 = 1 μmol/L) than EGFR (IC50 >500 μmol/L).target: TrKA [1], ErbB2 [2].IC 50: ErbB2 1 μmol/L [2].In vitro: TyrphostinAG879 significantly inhibit the A-type potassium currents in the cultured hippocampus neurons.[2] TyrphostinAG879 can reduce gephyrin puncta in GABAergic neurons and PSD-95 puncta in glutamatergic neurons where ErbB4 expression was low. [3] In vivo: Treatment with TyrphostinAG879 in immunodepressed mice graft with leiomyosarcoma or promyelocytic leukemia cells result in dramatic reductions in tumor sizes. [1]

LH846 is a selective inhibitor of CK1δ (IC50 values are 290 nM, 1.3 uM and 2.5 uM for CK1δ, ε and α); displays no inhibitory activity at CK2.IC50 Value: 290 nM (CK1δ); 1.3 uM (CK1ε); 2.5 uM (CK1α) [1]Target: CK1 LH846 inhibits CK1δ-dependent phosphorylation and degradation of PER1 protein. Shown to lengthen the circadian period in U2OS cells, with minimal effect on amplitude.Treatment with LH846 reduced the PER1 mobility shift and PER1 clearance in a dose-dependent manner, indicating that CKIδ-dependent phosphorylation and subsequent degradation of PER1 protein is inhibited by LH846 treatment. Previous genetic studies demonstrated an important role of CKI-dependent phosphorylation of PER protein in period regulation, supporting the period lengthening effect of LH846 through PER1 protein phosphorylation [1].

1-Naphthyl PP1(1-NA-PP 1) is a selective inhibitor of src family kinases v-Src and c-Fyn as well as the tyrosine kinase c-Abl (IC50 values are 1.0, 0.6, 0.6, 18 and 22 μM for v-Src, c-Fyn, c-Abl, CDK2 and CAMK II respectively).IC50 Value:1.0 uM (v-Src); 0.6 uM (c-Fyn); 18 uM (c-Abl) [1]Target: Src Family kinase1-NA-PP1 was considerably more potent and showed distinct substituent effects at the pyrazolopyrimidine core. 1-NA-PP1 was cell-active, and potently blocked prostate cancer cell proliferation by inducing G2/M arrest. Overexpression of PKD1 or PKD3 almost completely reversed the growth arrest and the inhibition of tumor cell invasion caused by 1-NA-PP1, indicating that its anti-proliferative and anti-invasive activities were mediated through the inhibition of PKD. Interestingly, a 12-fold increase in sensitivity to 1-NA-PP1 could be achieved by engineering a gatekeeper mutation in the active site of PKD1, suggesting that 1-NA-PP1 could be paired with the analog-sensitive PKD1(M659G) for dissecting PKD-specific functions and signaling pathways in various biological systems [2].

TWS119 is an inhibitor of glycogen synthase kinase-3β (IC50 = 30 nM). IC50 value: 30 nMTarget: GSK-3βTWS119 induces neuronal differentiation in pluripotent murine embryonal carcinoma cells and embryonic stem cells (ESCs).

PP-121 is a multi-targeted inhibitor of PDGFR, Hck, mTOR, VEGFR2, Src and Abl with IC50 of 2 nM, 8 nM, 10 nM, 12 nM, 14 nM and 18 nM, also inhibits DNA-PK with IC50 of 60 nM.IC50 value: 2/8/10/12/14/18 nM (PDGFR/Hck/mTOR/VEGFR/Src/Abl) [1]Target: PDGFR/Hck/mTOR/VEGFR/Src/AblPP-121 selectivity interacts within a hydrophobic pocket that is conserved between both tyrosine kinases and PI3Ks, not serine-threonine kinases. PP-121 makes a hydrogen bond to Glu310 in Src, effectively substituting for the structural role of the catalytic lysine and resulting in the ordering of helix C and stabilization of an active conformation. PP-121 also inhibits other PI3Ks including p110α and DNA-PK with IC50 of 52 nM and 60 nM, respectively. PP-121 potently and dose-dependently blocks the phosphorylation of Akt, p70S6K and S6 in two glioblastoma cell lines, U87 and LN229. PP-121 potently inhibits the proliferation of a subset of the tumor cell lines by direct inhibition of PI3Ks and mTOR. PP-121 induces a G0/G1 arrest in LN220, U87 and Seg1 cells. PP-121 also blocks tyrosine phosphorylation induced by v-Src in NIH3T3 cells transformed with v-Src(Thr338). PP-121 could restore actin stress fiber staining in NIH3T3 cells transformed with v-Src(Thr338). PP-121 at a low concentration of 40 nM inhibits Ret autophosphorylation in TT thyroid carcinoma cells that express the C634W oncogenic Ret mutant35. PP-121 inhibits cell proliferation with IC50 of 50 nM in TT thyroid carcinoma cells. PP-121 inhibits cell proliferating stimulated only with VEGF with IC50 of 41 nM in human umbilical vein endothelial cells (HUVECs). PP-121 directly inhibits Bcr-Abl induced tyrosine phosphorylation, resulting in drug-induced apoptosis in K562 cells and a combination of apoptosis and cell cycle arrest in Bcr-Abl expressing BaF3 cells.

SKLB1002 is a novel and potent VEGFR-2 inhibitor with an IC50 value of 32 nM.IC50 Value: 32 nM [1]Target: VEGFR-2in vitro: SKLB1002 showed potent inhibition of VEGFR2 kinase activity (IC50 = 32 nmol/L), which was similar with the positive drugs vandetanib (IC50 = 40 nmol/L) and sunitinib (IC50 = 9 nmol/L). SKLB1002 significantly inhibited endothelial cell proliferation with an IC50 value of 11.9 μmol/L. However, vandetanib and sunitinib inhibited cell viability at a much lower concentration with an IC50 value of 3.8 μmol/L and 1.9 μmol/L, respectively [1].in vivo: In vivo zebrafish model experiments showed that SKLB1002 remarkably blocked the formation of intersegmental vessels in zebrafish embryos. It was further found to inhibit a new microvasculature in zebrafish embryos induced by inoculated tumor cells. Finally, compared with the solvent control, administration of 100 mg/kg/d SKLB1002 reached more than 60% inhibition against human tumor xenografts in athymic mice [1]. Systemic treatment with SKLB1002 reduced symptoms of ear inflammation in K14/VEGF transgenic mice, the pathological score was significantly decreased, and acanthosis, focal parakeratosis, hyperkeratosis and hemangiectasis were improved. Furthermore, systemic treatment with SKLB1002 significantly reduced vascular abnormalities, permeability and T-cell infiltration [2].

PS-1145 is an IkappaB kinase (IKK) inhibitor with IC50 of 88 nM.IC50 value: 88 nM [1]Target: IKKin vitro: PS-1145 blocks TNFα-induced NF-κB activation in a dose- and time-dependent fashion in MM cells through inhibition of IκBα phosphorylation and degradation of IκBα, respectively. PS-1145 blocks the protective effect of IL-6 against Dex-induced apotosis. PS-1145 inhibits phosphorylation of IκBα in MM cells and modestly directly inhibits their growth. PS-1145 abrogates NF-κB activation related up-regulation of adhesion molecules on MM cells, MM cell to BMSC adherence, as well as the MM cell growth and survival advantage conferred both by adherence and cytokine secretion in the BM milieu.PS-1145 Inhibits IκBα Phosphorylation and NF-κB Activation in MM.1S Cells and Patient MM Cells.

Bupivacaine Hydrochloride is a local anaesthetic drug belonging to the amino amide group.Target: OthersBupivacaine hydrochloride is an effective local anesthetic agent. It has a rapid onset time, a high frequency of surgical anesthesia, a long duration, and a low incidence of side effects [1]. Median doses of bupivacaine (in milligrams per kilogram) producing asystole in protocol 1 were for 17.7 for saline, 27.6 for 10% Intralipid, 49.7 for 20% Intralipid, and 82.0 for 30% Intralipid (P < 0.001 for differences between all groups). Differences in mean +/- SE concentrations of bupivacaine in plasma (in micrograms per milliliter) were significant (P < 0.05) for the difference between saline (93.3 +/- 7.6) and 30% Intralipid (212 +/- 45). In protocol 2, lipid infusion increased the dose of bupivacaine required to cause death in 50% of animals by 48%, from 12.5 to 18.5 mg/kg. The mean lipid:aqueous ratio of concentrations of bupivacaine in a plasma-Intralipid mixture was 11.9 +/- 1.77 (n = 3) [2].

XL413 is a potent and selective Cdc7 inhibitor with an IC50 of 3.7 nM, >60-fold selectivity against CK2, >10-fold selectivity against PIM, and >300-fold selectivity against a panel of over 100 protein kinases. Phase 1IC50 value: 3.7 nM [1]Target: Selective Cdc 7XL413 demonstrated excellent plasma exposures in mice [100 mg/kg (PO): 141 lM (1 h), 81 lM (4 h)]. Prolonged treatment with XL413 (3 days) inhibited the cell proliferation (IC50 = 2685 nM), decreased cell viability (IC50 = 2142 nM) and elicited the caspase 3/7 activity (EC50 = 2288 nM) in Colo-205 cells.XL413 demonstrated an excellent exposure profile infull rat PK assay (dosed at 3 mg/kg: Cmax (PO) = 8.61 lM, AUC(po) = 75 lM h, CL = 117 mL/h kg, Vss = 0.55 L/kg, T1/2 = 2.32 h, F = 95%). Tumor bearing mice were administered XL413 orally at doses of 10, 30, or 100 mg/kg once daily (qd) for 14 days,XL413 was well tolerated at all the doses and regimens examined, with no significant body weight loss observed [1].

Kenpaullone is an ATP-competitive inhibitor of several CDKs as well as GSK-3β, with an IC50 value of 0.23 μM for GSK-3β and 0.4, 0.68, 0.85, and 0.47 μM for CDK1/cyclin B, CDK2/cyclin A, CDK5/p25, and lymphocyte kinase., respectively. IC50 value: 0.23 μM (GSK-3β), 0.4 μM (CDK1/cyclin B), 0.68 μM (CDK2/cyclin A), 0.85μM (CDK5/p25), and 0.47 μM ( lymphocyte kinase)Target: CDK, GSK-3in vitro: Kenpaullone is useful in the study of cell cycle regulators. Kenpaullone is an inhibitor of cyclin E, ERK 2 and p35. Kenpaullone is able to replace Klf4 in the reprogramming of primary and secondary fibroblasts and NPCs.FR 180204 is an ATP-competitive, selective ERK inhibitor with Ki of 0.31 μM and 0.14 μM for ERK1 and ERK2, respectively.Fasudil (Hydrochloride) is a potent inhibitor of ROCK-II, PKA, PKG, PKC, and MLCK with KI of 0.33 μM, 1.6 μM, 1.6 μM, 3.3 μM and 36 μM, respectively.

PD158780 is a very potent inhibitor of EGFR with IC50 of 0.08 nM; pan-specific antagonist of ErbB receptor.IC50 value: 0.08 nM [1]Target: EGFR inhibitorin vitro: PD158780 potently inhibited the LPA-stimulated MAP kinase kinase 1/2 (MKK1/2) activation and EGF receptor tyrosine phosphorylation in HeLa cells, while it had no detectable effect on c-Src kinase activity. PD158780 also inhibited LPA-induced MKK1/2 activation and DNA synthesis in NIH 3T3 cells. Furthermore, we compared LPA-stimulated MKK1/2 and MAP kinase activation, transcriptional activity of the c-fos promoter, and DNA synthesis in B82L cells, which lack endogenous EGF receptor, and B82L cells expressing kinase-defective or wild-type human EGF receptor [2]. in vivo: NRG-1beta dramatically increases gamma oscillation power in hippocampal slices from both rats (2062 +/- 496%) and mice (710 +/- 299%). These effects of NRG-1beta are blocked by PD158780, a pan-specific antagonist of ErbB receptors, and are mediated specifically via ErbB4 receptors, because mice harboring a targeted mutation of ErbB4 do not respond to NRG-1 [3].

TTP 22 is a high affinity, ATP-competitive casein kinase 2 (CK2) inhibitor with IC50/Ki of 0.1 uM/40 nM; shows selectivity for CK2 over JNK3, ROCK1, and MET(IC50> 10 uM).IC50 Value: 0.1 uMTarget: CK2TTP 22 shows selectivity for CK2 over JNK3, ROCK1, and MET (inhibitory effects displayed at greater than 10 μM). TTP 22 is highly conserved serine/threonine protein kinase that is also involved in cell proliferation, cell differentiation and apoptosis.SB 202190 inhibits p38 and p38β2 with IC50 values of 50 nM and 100 nM. respectively.

1-NM-PP1 inhibits Cdk7 recovered from the mutant, but not the wild-type cells with an IC50 of ~50 nM with either substrate.

KW-2449 is a multiple-targeted inhibitor, mostly for Flt3 with IC50 of 6.6 nM, modestly potent to FGFR1, Bcr-Abl and Aurora A; little effect on PDGFRβ, IGF-1R, EGFR. IC50 value: 6.6 nM [1]Target: Flt3in vitro: Phosphorylation levels of FLT3 and STAT5 are decreased by KW-2449 in a dose-dependent manner. In addition, it potently inhibits ABL-T315I, which is associated with IM resistance, with IC50 of 4 nM. On the other hand, KW-2449 has little effect on PDGFRβ, IGF-1R, EGFR, and various serine/threonine kinases even at a concentration of 1 μM. KW-2449 has the potent growth inhibitory activities against not only FLT3/ITD-expressing leukemia cells but also FLT3/KDM-activated and wild-type FLT3-overexpressing leukemia cells [1]. KW-2449 is rapidly absorbed and converted to a major metabolite M1.Preclinical studies reveal that KW-2449 is converted by monoamine oxidase-B (MAO-B) and aldehyde oxidase into its major metabolite M1.KW-2449 mediates cytotoxicity thru inhibition of FLT3/ITD.KW-2449 is a direct inhibitor of FLT3 and induces inhibition of its downstream target STAT5 [2]. KW2449 interacts synergistically with HDACIs to induce apoptosis in Ph+ CML cells in a time- and concentration-dependent manner. KW2449 synergistically enhances the lethality of vorinostat/SNDX275 in CML cells.KW-2449 regimens are active against additional IM-resistant Bcr/Abl+ leukemia cells. KW2449 moderately reduces phosphorylation of histone H3, an indicator of Aurora B activity, in nocodozole-treated K562 cells [3]. in vivo: In the MOLM-13 tumor xenograft model, oral administration of KW-2449 for 14 days shows a potent and significant antitumor effect in a dose-dependent manner [1].

TCS JNK 5a(JNK Inhibitor IX) is a selective inhibitor of JNK2 and JNK3 (pIC50 values are 6.7, 6.5, <5.0 and <4.8 for JNK3, JNK2, JNK1 and p38α respectively); displays no significant activity at a range of other protein kinases including EGFR, ErbB2, cdk2, PLK-1 and Src (pIC50 < 5.0).IC50 value: 6.7/6.5(pIC50, JNK3/JNK2)Target: JNK2/3Oglufanide inhibits vascular endothelial growth factor (VEGF), which may inhibit angiogenesis.This agent has also been reported to stimulate the immune response to hepatitic C virus and intracellular bacterial infections.ZM-306416(CB 676475) is a VEGFR inhibitor that inhibits Flk-1 (KDR) (IC50=100 nM) and Flt (IC50 =2 μM); displays 4-fold selectivity over FGFR-1; inhibitor of c-Abl, Flt-1 and Src.IC50 Value: 0.67uM(VEGFR); 0.33±0.08uM(Src); 1.3±0.2 μM(Abl)Target: VEGFR; Src; Ablin vitro: 306416 was found to be very potent toward the EGFR kinase with an IC50 value lower than 10 nM, reaching our assay detection limit and confirming our result using the EGFRB assay. ZM-306416 exhibited inhibitory activity across all three kinases of the panel, yielding IC50 values of 0.33±0.08 μM for SRC, 0.33±0.04 μM for VEGFR1, and 1.3±0.2 μM for ABL kinases [1].

GDC-0879 is a novel, potent, and selective B-Raf inhibitor with IC50 of 0.13 nM with activity against c-Raf as well; no inhibition known to other protein kinases.IC50 value: 0.13 nM [1]Target: B-Rafin vitro: GDC-0879 also inhibits cellular pERK with IC50 of 63 nM. GDC-0879 shows comparable potency in A375 melanoma and Colo205 colorectal carcinoma cell lines, both of which are B-RafV600E mutant, with IC50 of 59 nM and 29 nM for pMEK1 inhibition respectively. GDC-0879 potently inhibits B-RafV600E in Malme3M cells with IC50 of 0.75 μM. GDC-0879 also shows EC50 values < 0.5 μM in many tumor cells (A375, 624, SK-MEL-28, Malme3M, C32, 928, 888, G-361, Colo205, Colo206, SW1417, CL34, and Colo201) [1].in vivo: In GDC-0879 treated mice, both cell line- and patient-derived BRAFV600E tumors exhibit stronger and more sustained pharmacodynamic inhibition (>90% for 8 hours) and improved survival compared to mutant KRAS-expressing tumors. Although there is involvement of activated RAF signaling in RAS-induced tumorigenesis, decreased time to progression is observed for some KRAS-mutant tumors following GDC-0879 administration. Whereas GDC-0879-mediated efficacy is associated strictly with B-RafV600E status, MEK inhibition also attenuates proliferation and tumor growth of cell lines expressing wild-type BRAF (81% KRAS mutant, 38% KRAS wild type). The responsiveness of B-RafV600E melanoma cells to GDC-0879 could be dramatically altered by pharmacologic and genetic modulation of PI3K pathway activity [2].

Tideglusib is an irreversible GSK-3 inhibitor with IC50 of 5 nM and 60 nM for GSK-3βWT (1 h preincubation) and GSK-3βC199A (1 h preincubation), respectively.SL-327 is a cell-permeable vinylogous cyanamide that acts as a selective inhibitor of MEK-1 and MEK-2 (IC50 = 0.18 and 0.22 μM respectively). IC50 value: 0.18/0.22 uM(MEK1/2)Target: MEK1/2SL-327 has been shown to block hippocampal LTP via inhibition of the MAPK/ERK cascade, which prevents CREB and Elk-1 phosphorylation, and LTP-dependent gene induction, resulting in rapidly decaying LTP, while being uncompetitive with respect to ATP. Brain penetrant in vivo, blocking fear conditioning and learning in rats, and producing neuroprotection in mice, following systemic administration. SL-327 has also been shown to inhibit ERK1, MEK-3/p38, MEK-4, JNK, and PKC activities when used at higher concentrations.DPH is a potent cell permeable c-Abl activator, which displays potent enzymatic and cellular activity in stimulating c-Abl activation. CC-115 is a inhibitor of mTOR/DNA-PK (IC50= 21/ 13 nM).IC50 value: 21 nM (for mTOR), 13 nM (for DNA-PK)Target: mTOR, DNA-PKin vitro: The IC50 values for CC-115 are >10 μM against a panel of CYP enzymes and >33 μM for the hERG ion channel. When screened in a single point assay at 10 μM against a Cerep receptor and enzyme panel only one target was inhibited >50% (PDE3, IC50 = 0.63 μM). in vivo: CC-115 shows good PK profiles across multiple species with 53%, 76%, and 100% oral bioavailability in mouse, rat, and dog, respectively. CC-115, with favorable physicochemical and pharmacokinetic properties, demonstrates mTOR pathway inhibition and tumor growth inhibition, as well as a good safety profile, suitable for clinical development.

AT7867 is a potent ATP-competitive inhibitor of Akt1/2/3 and p70S6K/PKA with IC50 of 32 nM/17 nM/47 nM and 85 nM/20 nM, respectively; little activity outside the AGC kinase family.IC50 value: 32 nM/17 nM/47 nM(Akt1/2/3) [1]Target: Aktin vitro: AT7867 also inhibits structurally related AGC kinases p70S6K and PKA with IC50 of 20 nM and 85 nM, respectively. AT7867 shows ATP-competitive activity to Akt2 with Ki of 18 nM. AT7867 exhibits antiproliferation in cell lines with PTEN or PIK3CA mutations and shows great potent to MES-SA, MDA-MB-468, MCF-7, HCT116 and HT29 with IC50 of 0.94 μM, 2.26 μM, 1.86 μM, 1.76 μM and 3.04 μM, respectively. AT7867 also suppresses the cell growth of U87MG, PC-3 and DU145 cells with IC50 of 8.22 μM, 10.37 μM and 11.86 μM, respectively. AT7867 suppresses Akt activity by inhibiting phosphorylation of GSK-3β in human tumor cells with IC50 of 2-4 μM. AT7867 also induces the phosphorylation of the following Akt direct substrates including proapoptotic transcription factors FKHR (FoxO1a), FKHRL1 (FoxO3a) and the downstream target S6RP in U87MG cells.in vivo: AT7867 shows bioavailability of 44% in mice by p.o. route. AT7867 could increase the cleaved PARP in MES-SA xenografts at 20 mg/kg i.p. or 90 mg/kg p.o.. AT7867 significantly inhibits the tumor growth in MES-SA xenografts or U87MG xenografts with T/C of 0.37 and 0.51, respectively.

NVP-BVU972 is a selective and potent Met inhibitor (IC50 = 14 nM). Antitumor agents.IC50 value: 14 nM [1]Target: MetNVP-BVU972 potently inhibits MET kinase but displays low inhibition against other kinases including the most closely related kinase RON with IC50 values of more than 1000 nM. NVP-BVU972 also suppresses constitutive MET phosphorylation in GTL-16 cells or HGF-stimulated MET phosphorylation in A549 cells with IC50 values of 7.3 nM and 22 nM, respectively. NVP-BVU972 potently prevents the growth of the MET gene amplified cell lines GTL-16, MKN-45 and EBC-1 with IC50 values of 66 nM, 82 nM and 32 nM, respectively. In line with their high frequency in the NVP-BVU972 screen, Y1230 and D1228 mutations give rise to dramatic shifts in the measured IC50 values for NVP-BVU972 in BaF3 cell line. Resistance triggered by V1155L is more limited to NVP-BVU972. A dose-dependent reduction in TPR-MET phosphorylation when applying NVP-BVU972 to BaF3 cells expressing wild-type TPR-MET. Both Y1230H and D1228A mutations abrogated the effect of NVP-BVU972 but not AMG 458. However, F1200I and L1195V interferes with the potency of NVP-BVU972 to prevent TPR-MET phosphorylation.

PQ401, a selective insulin-like growth factor-1 receptor blocker, is a novel diarylurea compound that inhibits IGF1R autophosphorylation with IC50 < 1 uM.IC50 Value: 12 uM (inhibited autophosphorylation of the IGF-IR in cultured human MCF-7 cells) [1]Target: IGF1Rin vitro: PQ401 inhibited autophosphorylation of the IGF-IR in cultured human MCF-7 cells with an IC50 of 12 micromol/L and autophosphorylation of the isolated kinase domain of the IGF-IR with an IC50 <1 micromol/L. In addition,PQ401 inhibited the growth of cultured breast cancer cells in serum at 10 micromol/L. PQ401 was even more effective at inhibiting IGF-I-stimulated growth of MCF-7 cells (IC50, 6 micromol/L) [1]. Twenty-four hours of treatment with 15 micromol/L PQ401 induced caspase-mediated apoptosis. Pretreatment with PQ401 before IGF-1 (10 ng in 0.5 μl), both administered to the POA 30 min apart, showed significant attenuation of the IGF-1-induced increase in core body temperature (p < 0.05). A similar attenuated hyperthermic response to IGF-1 by PQ401 pretreatment is observed when the temperature of the BAT is measured [3].in vivo: IGF1R inhibition by PQ401 exerted no significant effects on diabetic kidney disease parameters, arguing against a role for IGF-I in the pathogenesis of diabetic kidney disease. However, PQ401 affects normal kidneys, inducing renal hypertrophy as well as collagen and fat accumulation, with increased renal IGF-I mRNA, suggestive of a damage-regeneration process [2].Clinical trial: No Development Reported

CCT128930 is a novel potent ATP-competitive, selective Akt2 inhibitor with an IC50 of 6 nM; >28-fold selectivity for Akt2 than the closely related PKA kinase.IC50 value: 0.6 nMTarget: Akt2CCT128930 prevents AKT activity in vitro and in vivo and induces marked antitumor responses. CCT128930 showed significantly antiproliferative activity and inhibited the phosphorylation of a range of AKT substrates in multiple tumor cell lines in vitro, consistent with AKT inhibition. CCT128930 caused a G1 arrest in PTEN-null U87MG human glioblastoma cells, in good agreement with AKT pathway blockade.Fingolimod hydrochloride is a sphingosine 1-phosphate (S1P) antagonist with IC50 of 0.033 nM in K562 and NK cells.

ETC-1002 (ESP-55016) is an activator of hepatic AMP-activated protein kinase (AMPK); also an inhibitor of hepatic ATP-citrate lyase (ACL) with an IC50 of 29 μM.

TG100–115 is a PI3K γ and -δ inhibitor (IC50 = 83 and 235 nM, respectively)

CX-4945 is an orally bioavailable, highly selective and potent CK2 inhibitor, with IC50 values of 1 nM against CK2α and CK2α'.IPA-3 is a selective non-ATP competitive PAK1 inhibitor with IC50 of 2.5 μM, and shows no inhibition to group II PAKs (PAKs 4-6).

ISCK03 is a specific SCF/c-Kit inhibitor.Coptisine (chloride) is a natural product.

AICAR phosphate is an activator of AMP-activated protein kinase (AMPK), down-regulates the insulin receptor expression in HepG2 cells.

A-769662 is a potent, reversible AMPK activator with EC50 of 0.8 μM, and has little effect on GPPase/FBPase activity.

PF06650833 is an inhibitor of Interleukin-1 receptor associated kinase 4 (IRAK4), and used to treat diseases such as rheumatoid arthritis, lupus, and lymphomas.

EMD638683 is a highly selective SGK1 inhibitor with IC50 of 3 μM.

TGX-221 is a potent, selective, and cell membrane permeable inhibitor of the PI3K p110β catalytic subunit, used for cancer treatment.SC79 is a brain-penetrable Akt phosphorylation activator and an inhibitor of Akt-PH domain translocation.

BMS-265246 is a potent and selective CDK1/2 inhibitor for CDK1/cyclin B and CDK2/cyclin E with IC50 of 6 nM and 9 nM, respectively. IC50 Value: 6 nM(for CDK1/cyclin B); 9 nM(for CDK2/cyclin E)Target: CDK1/2in vitro: BMS-265246 inhibits the activity of Cdk4/cycD (IC50 = 0.23 μM) and prevents A2780 Cytox with IC50 of 0.76 μM. BMS-265246 when bound to Cdk2, shows the inhibitor resides within the ATP purine binding site and forms important H-bonds with Leu83 on the protein backbone. BMS-265246 represents the most potent Cdk/Cdk2 selective analogue from this chemotype. A recent study shows that BMS-265246 inhibits cell proliferation with EC50 ranging from 0.293 μM-0.492 μM in HCT-116 cells. After treatment of BMS-265246, the dominant cell populations are G2-arrested cells having 4N DNA content, large round nuclei, and low DNA intensity.in vivo:

SSR128129E is a multi-FGFR blocker with allosteric properties; inhibits FGFR signaling by binding to the extracellular FGFR domain without affecting orthosteric FGF binding.IC50 value: 31±1.6 nM(FGF2-induced EC proliferation) [1]Target: FGFR blockerin vitro: SSR inhibited FGFR-driven responses while not affecting other related RTKs. SSR128129E inhibits fibroblast growth factor receptor (FGFR) signaling by binding to the extracellular FGFR domain without affecting orthosteric FGF binding. SSR exhibits allosteric properties, including probe dependence, signaling bias, and ceiling effects [1].in vivo: Oral delivery of SSR inhibits arthritis and tumors that are relatively refractory to anti-vascular endothelial growth factor receptor-2 antibodies [1]. Four-week old male apoE-deficient mice were treated with SSR128129E (50 mg/kg/d) for 3 and 5 months in comparison with a control group. SSR128129E treatment resulted in a reduction of lesion size in the aortic sinus (16.4% (ns) at 3 months and 42.9% (p<0.01) at 5 months, without any change in serum lipids. SSR128129 significantly reduced FGFR2 mRNA levels in the aortic sinus (p<0.05, n=5-6), but did not affect the mRNA expression levels of other FGF receptors or ligands [2].

NG 52 (Compound 52 ) is a potent, cell-permeable, reversible, selective, and ATP-compatible inhibitor of the cell cycle-regulating kinase, Cdc28p (IC50 = 7 μM), and the related Pho85p kinase (IC50 = 2 μM).IC50 value: 7 uM [1]Target: Cdc28pCompound 52 inhibited growth in a drug-sensitized yeast strainwith a GI 50 of 30 uM. In contrast, the closely related compound 52Me proved to be a significantly weaker inhibitor of yeast growth (GI50=200 uM).

L-779450 is a potent, ATP-competitive Raf kinase inhibitor (IC50 =10 nM) that displays > 7, > 30 and > 70-fold selectivity over p38α, GSK3β and Lck respectively.IC50 value:Target: Raf inhibitorL-779450 suppressed DNA synthesis and induced apoptosis in hematopoietic FDC-P1 cells transformed to grow in response to either Raf-1 or A-Raf (FD/DeltaRaf-1:ER and FD/DeltaA-Raf:ER), but it displayed less effects on DNA synthesis and apoptosis when the cells were cultured in IL-3. L-779450 was less effective on B-Raf- or MEK1-responsive cells [1]. Treatment with L779450, but not PLX4720, induced strong KSR1/B-Raf binding in A549 and HMCB cells that possess oncogenic Ras proteins, in the Cal12T line that contains an impaired activity B-Raf mutant, and, surprisingly, in A375 melanoma cells that are homozygous for V600E-B-Raf. L779450-induced B-Raf/C-Raf dimerization was not reduced in MEFs expressing the R615H- and C809Y-KSR1 mutants unable to bind B-Raf; whereas B-Raf/C-Raf dimerization was abolished in cells expressing S297A/S392A-KSR1 that exhibits enhanced inhibitor-induced B-Raf binding [3].

Ingenol is an extremely weak PKC (protein kinase C) activator; has been found to induce apoptosis and act as an anticancer agent. IC50 value:Target: anticancer natural compoundin vitro: ingenol indeed binds to protein kinase C with a Ki of 30 microM and activates the enzyme. In addition, ingenol was biologically active in 3 separate cell systems, showing effects similar to the phorbol esters on morphological change, cell-cell communication, epidermal growth factor binding, arachidonic acid metabolite release, and ornithine decarboxylase activity [1].

CP-466722 is rapidly reversible potential ATM kinase inhibitor.IC50 Value:Target: ATMCP-466722 is non-toxic and does not inhibit PI3K or PI3K-like protein kinase family members in cells. CP-466722 inhibited cellular ATM-dependent phosphorylation events and disruption of ATM function resulted in characteristic cell cycle checkpoint defects. Inhibition of cellular ATM kinase activity was rapidly and completely reversed by removing CP-466722. Interestingly, clonogenic survival assays demonstrated that transient inhibition of ATM is sufficient to sensitize cells to ionizing radiation and suggests that therapeutic radiosensitization may only require ATM inhibition for short periods of time. The ability of CP-466722 to rapidly and reversibly regulate ATM activity provides a new tool to ask questions about ATM function that could not easily be addressed using genetic models or RNA interference technologies.

SRPIN340 is a serine/arginine-rich protein kinase (SRPK)-specific inhibitor with an IC50 value of 0.89 uM (SRPK1); no significant inhibitory activity against more than 140 other kinases.IC50 Value: 0.89 uM (SRPK1) [1]Target: SRPKin vitro: SRPIN340 potently inhibits SRPK1 kinase activity, with a Kivalue of 0.89 μM. SRPIN340 inhibits SR phosphorylation by SRPK in Flp-In293 cells and promotes degradation of SRp75 in a dose-dependent manner (Fig. 4). Thus, because retention of SRp75 is necessary for HIV expression, SRPIN340 emerges as a potential inhibitor of HIV production. SRPIN340 (40 μM) rescues Vero cells from the cytopathic effect of Sindbis virus. The SRPIN340 IC50 for Sindbis virus propagation was 60 μM [1]. SRPIN340, suppressed in a dose-dependent fashion expression of a hepatitis C virus (HCV) subgenomic replicon and replication of the HCV-JFH1 clone in vitro. The inhibitory effects were not associated with antiproliferative or nonspecific cytotoxic effects on the host cells. Overexpression of SRPK1 or SRPK2 resulted in augmentation of HCV replication, while small interfering RNA (siRNA) knockdown of the SRPKs suppressed HCV replication significantly [2]. SRPIN340 inhibited CNV formation in a dose-dependent manner. Compared with the vehicle, SRPIN340 significantly decreased the protein levels of VEGF, MCP-1, ICAM-1, and consequently inhibited macrophage infiltration. Furthermore, SRPIN340 suppressed the gene expression levels of total Vegf and exon 8a-containing Vegf isoforms [3].in vivo: No adverse effects were observed when SRPIN340 was orally administrated to rats, even at the highest SRPIN340 dose (2,000 mg/kg). In addition, no abnormalities in chromosomal structure and chromosome number were observed when SRPIN340 was administrated to CHO cells in the culture medium at the highest SRPIN340 dose (5 mg/ml) for 24 h [1].Toxicity: The rudimentary toxicity data available for SRPIN340 is promising with respect to the potential for use of this compound as a therapeutic. No adverse effects were observed when SRPIN340 was orally administrated to rats, even at the highest SRPIN340 dose (2,000 mg/kg). In addition, no abnormalities in chromosomal structure and chromosome number were observed when SRPIN340 was administrated to CHO cells in the culture medium at the highest SRPIN340 dose (5 mg/ml) for 24 h [1]. Clinical trial:

TA-01 potently inhibits CK1ε, CK1δ,and p38α (IC50values are 6.4, 6.8, and 6.7 nM respectively).IC50 value: 6.4/6.8/6.7 nMTarget: CK1ε/ CK1δ/p38α MAPKin vitro: TA-01 inhibitors inhibit cardiac development when applied at 5 μM. TA-01 shows an almost complete inhibition of cardiogenesis when applied at 5 μM. TA-01 shows reduced expression of all tested mesoderm markers and the pre-cardiac marker Isl-1.

Ro-3306 is a potent and selective inhibitor of CDK1 with Ki value of 35 nM for CDK1/cyclin B1, 10-fold selectivity relative to CDK2/cyclin E and >50-fold relative to CDK4/cyclin D.IC50 value: 35 nM (Ki) [1]Target: CDK1 inhibitor in vitro: Ro-3306 also inhibited CDK1/cyclin A complexes with Ki of 110 nM. In full agreement with this model, treatment of proliferating human cancer cells (HCT116, SW480, and HeLa) with RO-3306 for 20 h led to a complete block of the cell cycle in the G2/M phase [1]. Treatment of growing AML cells with RO-3306 induced G2/M-phase cell cycle arrest and apoptosis in a dose- and time-dependent manner. RO-3306 acts cooperatively with Nutlin-3 to induce mitochondrial apoptosis in a cell cycle-independent fashion. RO-3306 downregulated expression of the antiapoptotic proteins Bcl-2 and survivin and blocked p53-mediated induction of p21 and MDM2 [2]. The GV-arrest effect of RO-3306 was reversible: when RO-3306-arrested COCs were subsequently cultured for 24h in the absence of RO-3306, 76.19 ± 2.68% of these oocytes reached the MII stage after 44 h of in vitro maturation, a rate similar to that of non-treated control oocytes (79.08 ± 3.23%). Furthermore, RO-3306-treated oocytes transferred to drug-free media did not differ significantly from controls (P>0.05) with respect to cleavage and blastocyst formation upon parthenogenetic activation [3].

1-Naphthyl PP1(1-NA-PP1) hydrochloride is a selective inhibitor of src family kinases v-Src and c-Fyn as well as the tyrosine kinase c-Abl (IC50 values are 1.0, 0.6, 0.6, 18 and 22 μM for v-Src, c-Fyn, c-Abl, CDK2 and CAMK II respectively).IC50 Value:1.0 uM (v-Src); 0.6 uM (c-Fyn); 18 uM (c-Abl) [1]Target: Src Family kinase1-NA-PP1 was considerably more potent and showed distinct substituent effects at the pyrazolopyrimidine core. 1-NA-PP1 was cell-active, and potently blocked prostate cancer cell proliferation by inducing G2/M arrest. Overexpression of PKD1 or PKD3 almost completely reversed the growth arrest and the inhibition of tumor cell invasion caused by 1-NA-PP1, indicating that its anti-proliferative and anti-invasive activities were mediated through the inhibition of PKD. Interestingly, a 12-fold increase in sensitivity to 1-NA-PP1 could be achieved by engineering a gatekeeper mutation in the active site of PKD1, suggesting that 1-NA-PP1 could be paired with the analog-sensitive PKD1(M659G) for dissecting PKD-specific functions and signaling pathways in various biological systems [2].

VS-5584 (SB2343) is a potent and selective dual PI3K/mTOR inhibitor for mTOR, PI3Kα/β/δ/γ with IC50 of 3.4 nM and 2.6-21 nM, respectively.IC50 value: 3.4 nM/2.6 nM/3.3 nM/21 nM/2.7 nM/3.0 nM (mTOR/PI3Kα/PI3Kα-H1047/PI3Kβ/PI3Kδ/PI3Kγ) [1]Target: mTOR/PI3Kin vitro: VS-5584 is an ATP-competitive inhibitor which selectively inhibits PI3K/mTOR signaling with equivalent low nanomolar potency against all human Class I PI3K isoforms and mTOR kinase. VS-5584 is approximately 10-fold selective for cancer stem cells with an EC50 of 15 nM in HMLE breast cancer cells. VS-5584 preferentially decreases CD44Hi/CD24Lo cells in an HMLER immortalized mammary cancer cell line. In SUM159 cells, VS-5584 effectively eliminates the cancer stem cell side population [1]. A large human cancer cell line panel screen (436 lines) reveals broad antiproliferative sensitivity and that cells harboring mutations in PI3KCA are generally more sensitive toward VS-5584 treatment. In the FLT3-ITD harboring MV4-11 cells, VS-5584 blocks pAkt (S473) and pAkt (T308) with IC50 of 12 and 13 nM, respectively. The IC50 of VS-5584 for pS6 (S240/244), pAkt (S473), and pAkt (T308) are 20, 23, and 15 nM, respectively [2].in vivo: In mice bearing triple negative breast cancer tumors, oral dosing of VS-5584 decreases tumor cancer stem cells and induces tumor regression in taxane-resistant models [1]. In a PTENnull human prostate PC3 xenograft model, treatment with VS-5584 leads to significant tumor growth inhibition (TGI) of 79% and 113% for 11 and 25 mg/kg, respectively. In a FLT3-ITD AML xenograft model, VS-5584 treatment induces dose-dependent inhibition of tumor growth (28% for 3.7 mg/kg and 76% for 11 mg/kg) [2].

Roscovitine is a potent and selective CDK inhibitor with IC50 of 0.2 μM, 0.65 μM, and 0.7 μM for CDK5, Cdc2, and CDK2, respectively.

CGP60474 is a promising inhibitor of PKC with a high degree of selectivity versus other serine/threonine and tyrosine kinases and show competitive kinetics relative to ATP.IC50 value:Target: PKCBIO is a potent and selective inhibitor of GSK-3 and CDK1-cyclinB complex with IC50s of 5 nM/320 nM/83 nM for GSK-3αβ/CDK1/CDK5, respectively.CH5183284 is a selective and orally available FGFR1/2/3 inhibitor. The IC50 values of CH5183284 on the enzyme activity of FGFR1/2/3/4 were 9.3, 7.6, 22, and 290 nM, respectively. IC50 value: 9.3, 7.6, 22, and 290 nM (FGFR1/2/3/4) [1]Target: FGFRin vitro: The binding affinity (Kd) of CH5183284 for FGFR1, FGFR2, FGFR3, FGFR4, and KDR was 20, 20, 25, 740, and 960 nM, respectively (using the DiscoveRx panel). CH5183284 selectively inhibits FGFR1, FGFR2, and FGFR3 but does not inhibit kinase insert domain receptor (KDR) or other kinases. [1] CH5183284 shows antiproliferative activity against FGFR3-BAIAP2L1-positive cells only, including the bladder cancer cell line SW780, Rat-2_F3-B cells, and NIH-3T3 cells expressing FGFR3-BAIAP2L1, but not against NIH-3T3 cells expressing EML4-ALK (3T3_EML4-ALK) or HT1376 cells harboring WT FGFR. CH5183284/Debio 1347 induces apoptosis in SW780 and Rat-2_F3-B cells and suppresses FRS and ERK phosphorylation. [2]in vivo: CH5183284 shows significant antitumor activity against xenografts with FGFR genetic alterations. CH5183284 suppresses p-FGFR for at least 7 hours in SNU-16 xenograft tissue, as well as the downstream signaling, as indicated by a reduction in p-FRS, p-ERK, and p-S6. [1] CH5183284/Debio 1347 shows antitumor activity in SW780 and Rat-2_F3-B xenograft models, but not in WT FGFR HT1376 xenograft tumors. The downstream signals are suppressed in Rat-2_F3-B xenograft tumors treated by CH5183284/Debio 1347. [2]

R1530 is the multikinase inhibitor with potential antiangiogenesis and antineoplastic activities. IC50 Value: Target: VEGFR; PDGFRR1530 is also a mitosis-angiogenesis inhibitor (MAI) that inhibits multiple receptor tyrosine kinases involved in angiogenesis, such as vascular endothelial growth factor receptor (VEGFR)-1, -2, -3, platelet-derived growth factor receptor (PDGFR),Flt-3, and fibroblast growth factor receptor (FGFR) -1, -2. In addition, this agents exhibits anti-proliferative activity by initiating mitotic arrest and inducing apoptosis.in vitro: In the presence of R1530, polyploid cancer cells underwent apoptosis or became senescent which translated into potent in vitro and in vivo efficacy. Normal proliferating cells were resistant to R1530-induced polyploidy thus supporting the rationale for cancer therapy by induced polyploidy. Mitotic checkpoint kinase BubR1 was found downregulated during R1530-induced exit from mitosis, a likely consequence of PLK4 inhibition [1]. R1530 strongly inhibited human tumor cell proliferation. Growth factor-driven proliferation of endothelial and fibroblast cells was also inhibited [2].in vivo: Significant tumor growth inhibition was demonstrated in a lung cancer xenograft model with a range of once daily, weekly and twice-weekly doses of R1530 (3.125-50 mg/kg qd, 100 mg/kg qw, 100 mg/kg biw). Daily doses were most effective in the lung cancer model and also had significant growth inhibitory effects in models of colorectal, prostate, and breast tumors. Tumor regression occurred in all models treated with the maximum tolerated daily dose (50 mg/kg). The doses of 25 and 50 mg/kg qd resulted in biologically significant increased survival in all tested models. After oral administration in nude mice, R1530 showed good tissue penetration. Exposure was dose dependent up to 100 mg/kg with oral administration [2].Toxicity: N/AClinical trial: A Multiple Ascending Dose Study of R-1530 in Patients With Advanced Solid Tumors. Phase 1

TAS-301 is an inhibitor of smooth muscle cell migration and proliferation, inhibits intimal thickening after balloon injury to rat carotid arteriesTarget: PKCin vitro: TAS-301 displays a much more potent effect on neointimal formation than tranilast in the rat balloon injury model in terms of dosage and maximum efficiency and propose a possible mechanism of TAS-301 action based on the results of experiments on the migration and proliferation of vascular SMCs. TAS-301 inhibits the migration of smooth muscle cells (SMCs) stimulated by platelet-derived growth factor-BB, insulin-like growth factor-1 or heparin-binding epidermal growth factor-like growth factor. TAS-301 reduces the proliferation of medial and intimal SMCs at 4 and 8 days, respectively, after the injury. TAS-301 inhibits basic fibroblast growth factor-induced proliferation of SMCs dose dependently. TAS-301 shows a higher inhibitory potency on intimal formation than tranilast due to inhibition of both migration of medial SMCs and proliferation of medial and intimal SMCs. in vivo: TAS-301 is known to block intimal thickening post balloon injury in rat carotid arteries. It inhibits intimal thickening by blocking Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) and cytoskeletal depolymerization. TAS 301 can also inhibit receptor-regulated influx of calcium in rat vascular smooth muscle cells (VSMCs). Inhibitor of smooth muscle cell migration and proliferation. Blocks voltage-independent calcium influx and downstream PKC signaling. Inhibits neointimal thickening after balloon catheter injury to the rat common carotid artery.

SAR131675 is a VEGFR3 inhibitor with IC50/Ki of 23 nM/12 nM, about 50- and 10-fold more selective for VEGFR3 than VEGFR1/2, little activity against Akt1, CDKs, PLK1, EGFR, IGF-1R, c-Met, Flt2 etc.IC50 value: 23 nM [1]Target: VEGFR3in vitro: VEGFR-3 ligands VEGFC and VEGFD, with an IC50 of about 20 nM. SAR131675 dose dependently inhibits rh-VEGFR-3–TK activity with an IC50 of 23 nM. SAR131675 inhibits VEGR-3–TK activity with a Ki of about 12 nM. SAR131675 inhibits VEGFR-1–TK activity with an IC50 of > 3 μM and VEGFR-2–TK activity with an IC50 of 235 nM. SAR131675 inhibits VEGFR-1 autophosphorylation with an IC50 of about 1 μM and VEGFR-2 with an IC50 of about 280 nM. SAR131675 moderately inhibits VEGFR-2 and has very little effect on VEGFR-1, showing a good selectivity for VEGFR-3. SAR131675 inhibits VEGFA-induced VEGFR-2 phosphorylation in a dose-dependent manner, with an IC50 of 239 nM. SAR131675 potently inhibits lymphatic cell survival induced by VEGFC and VEGFD with IC50 of 14 nM and 17 nM, respectively. SAR131675 inhibits VEGFA-induced survival with an IC50 of 664 nM. SAR131675, significantly and dose dependently inhibits VEGFC-induced Erk phosphorylation, with an IC50 of about 30 nM [1].in vivo: In embryonic angiogenesis using the zebrafish model, SAR131675 efficiently impaires embryonic vasculogenesis. SAR131675 at 100 mg/kg/d has significantly reduced the levels of VEGFR-3 and hemoglobin content by about 50%. SAR131675 efficiently abrogates lymphangiogenesis and angiogenesis induced in vivo by FGF2. SAR131675 at a dose of 300 mg/kg is able to inhibit both VEGFR-2 and VEGFR-3 signaling. In the prevention study, 5 weeks treatment with SAR131675 is well tolerated and the number of angiogenic islets in the pancreas of SAR131675-treated mice is significantly decreased by 42%, compared with the vehicle-treated group. In the intervention study, daily oral administration of SAR131675 from week 10 to week 12.5 causes a significant decrease in tumor burden by 62%. Treatment with SAR131675 significantly reduces the tumor volume 24% and 50% at 30 mg/kg/d and 100 mg/kg/d, respectively [1].

SGX-523 is a selective Met inhibitor with IC50 of 4 nM, no activity to BRAFV599E, c-Raf, Abl and p38α.IC50 value: 4 nM [1]Target: Metin vitro: SGX-523 belongs to the class of c-Met/hepatocyte growth factor receptor (HGFR) tyrosine kinase inhibitors. SGX-523 stabilizes MET in a unique inactive conformation that is inaccessible to other protein kinases, suggesting an explanation for its selectivity. SGX523 potently inhibits the purified MET catalytic domain but not the closely related receptor tyrosine kinase RON. SGX523 indicates ATP-competitive inhibition with higher apparent affinity for the less active, unphosphorylated form of MET [MET-KD(0P), with a Ki of 2.7 nM] versus the more active phospho-enzyme [MET-KD(3P), with a Ki of 23 nM], a phenomenon consistent with preferential binding to an inactive enzyme conformation. SGX523 inhibits MET-mediated signaling, cell proliferation and cell migration at nanomolar concentrations but had no effect on signaling dependent on other protein kinases, including the closely related RON, even at micromolar concentrations [1].in vivo: SGX523 significantly retards the growth of preestablished GTL16 tumors when administered orally at doses of ≥10 mg/kg twice daily. SGX523 potently inhibits U87MG tumor growth; at 30 mg/kg dosed twice daily, SGX523 leads to clear regression of U87MG tumors. SGX523, dosed twice daily at 30 mg/kg, also retards the growth of H441 tumors with concomitant reduction in tumor MET autophosphorylation levels. SGX523 inhibition of MET in vivo is associated with the dose-dependent inhibition of growth of tumor xenografts derived from human glioblastoma, lung and gastric cancers, confirming the dependence of these tumors on MET catalytic activity [1].

SB 415286 is a potent and selective cell-permeable, ATP-competitive inhibitor of GSK3α with an IC50 value of 78 nM (similar potency for GSK3β) and a Ki value of 31 nM. IC50 value: 78 nMTarget: GSK3αAs a result of GSK3 inhibition, SB 415286 stimulates glycogen synthesis in the Chang human liver cell line with an EC50 value of 2.9 uM. SB 415286 also protects primary neurons from death induced by the PI3-kinase pathway.

LFM-A13 is a potent and selective inhibitor of Btk with IC50 of 17.2 uM; also inhibits PLK3 with IC50 of 7.2 uM.IC50 value:Target: Btk/PLK dual inhibitorin vitro: LFM-A13 inhibited recombinant BTK expressed in a baculovirus expression vector system with an IC50 value of 2.5 microM. Even at concentrations as high as 100 micrograms/ml (approximately 278 microM), this novel inhibitor did not affect the enzymatic activity of other protein tyrosine kinases, including JAK1, JAK3, HCK, epidermal growth factor receptor kinase, and insulin receptor kinase [1]. Inhibition of Btk activity by LFM-A13 leads to enhancement of PKCtheta; activity, whereas nonselective inhibition of PKC activity by bisindolylmaleimide I leads to reduction in Btk activity [2].in vivo: LFM-A13 suppressed migration and differentiation of osteoclast precursors as well as bone-resorbing activity of mature osteoclasts. In primary myeloma-bearing SCID-rab mice, LFM-A13 inhibited osteoclast activity, prevented myeloma-induced bone resorption and moderately suppressed myeloma growth [3].

PD153035(ZM 252868; AG 1517) is a potent and specific inhibitor of EGFR with Ki and IC50 of 5.2 pM and 29 pM; little effect against PGDFR, FGFR, CSF-1, InsR and Src.IC50 value: 5.2/29 pM(Ki/IC50) [1]Target: EGFRin vitro: PD 153035 shows a potent and selective inhibitory effect on tyrosine phosphorylation induced with EGF with IC50 of 15 nM and 14 nM in Swiss 3T3 fibroblast and A-431 human epidermoid carcinoma cells, respectively [1]. PD153035 shows growth inhibitory effects in cultures of EGF receptor-overexpressing human cancer cell lines including A431, Difi, DU145, MDA-MB-468 and ME180 cells with IC50 of 0.22 μM, 0.3μM, 0.4 μM, 0.68 μM and 0.95 μM, respectively [2]. in vivo: In A431 human epidermoid tumors grown as xenografts in immunodeficient nude mice, PD153035 at 80 mg/kg inhibit EGF receptor tyrosine kinase activity [3]. PD153035 improves glucose tolerance, insulin sensitivity, and signaling and reduces subclinical inflammation in HFD-fed mice [4].

PD 169316 is a potent, cell-permeable and selective p38 MAP kinase inhibitor (IC50 = 89 nM).IC50 Value: 89 nMTarget：p38 MAPKin vitro: PD169316, a p38 MAPK inhibitor, abrogates signaling initiated by both TGFbeta and Activin A, but not bone morphogenetic protein (BMP) 4. Inhibition of TGFbeta signaling is dose dependent and results in reduced Smad2 and Smad3 phosphorylation, nuclear translocation, and up-regulation of the TGFbeta target gene Smad7. Reduced TGFbeta signaling is not due to abrogation of p38 MAPK activity, since blocking p38 MAPK activity with a dominant negative form of p38 MAPK has no effect on TGFbeta/Smad signaling. PD169316 at 5 μM or higher can block TGFβ signaling activity and thus caution must be used when attributing cellular activities exclusively to p38 MAPK signaling when these inhibitors are used experimentally [1]. PD169316 significantly attenuated apoptosis in potassium-deprived cells in a dose dependent manner [2]. PD169316 rescued the inhibitory effect of sphingosine on the formation of inositol phosphates by PGF(2alpha) or NaF in osteoblast-like MC3T3-E1 cells [3]. 6-keto-PGF(1alpha) release was increased in a concentration-dependent manner following LPS exposure (maximal at 10(-6)g/ml; EC(50) = 1 x 10(-9)g/ml), and was significantly inhibited by p38 MAPK blockade (reduced from 1.6+/-0.3 x 10(-9)g/ml to 4+/-1 x 10(-10)g/ml and 4+/-2 x 10(-10)g/ml with 10(-6) M SB203580 or 10(-6) M PD169316, respectively) [4].

TCS 359, a 2-acylaminothiophene-3-carboxamide, is a potent inhibitor of FLT3 with IC50 of 42 nM. IC50 Value: 42 nM [1]Target: Flt3in vitro: TCS 359, a 2-acylaminothiophene-3-carboxamide, is a potent inhibitor of FLT3 with IC50 of 42 nM. TCS 359 inhibits MV4-11 proliferation with IC50 of 340 nM. TCS 359 is highly selective for FLT3 against a panel of kinases [1].

PHA-793887 is a novel pan-cdk inhibitor, including cdk1, cdk2, cdk4, cdk5, cdk7, and cdk9 with IC50 in the 5 to 140 nM range.IC50 Value: 8 nM (CDK2), 5 nM(CDK5), 10 nM (CDK7)Target: CDKsin vitro: PHA-793887 is cytotoxic for leukemic cell lines, including K562, KU812, KCL22, and TOM1, with IC50 of 0.3-7 μM, but it is not cytotoxic for normal unstimulated peripheral blood mononuclear cells or CD34+ hematopoietic stem cells. In colony assays, PHA-793887 shows very high activity against leukemia cell lines with IC50 less than 0.1 μM. PHA-793887 induces cell-cycle arrest, inhibits Rb and nucleophosmin phosphorylation, and modulates cyclin E and cdc6 expression at 0.2-1 μM and induces apoptosis at 5 μM. PHA-793887 has low activity against CDK1, CDK4, CDK9 and GSK3β with IC50 of 60 nM, 62 nM, 138 nM and 79 nM, respectively. PHA-793887 inhibits cell proliferation of many tumor cell lines, including A2780, HCT-116, COLO-205, C-433, DU-145, A375, PC3, MCF-7, and BX-PC3, with IC50 of 88 nM-3.4 μM. PHA-793887 (1 μM) shows a decrease in the S phase, a subsequent increase of the G1 phase and a slight accumulation of G2/M phase in A2780 cells. PHA-793887 (3 μM) significantly increases G2/M phase and reduces DNA synthsis. in vivo: PHA-793887 (20 mg/kg) is effective in xenograft models of K562 and HL60 cells, primary leukemic disseminated model, and a high-burden disseminated ALL-2 model derived from a relapsed Philadelphia-positive acute lymphoid leukemia patient. PHA-793887 (10-30 mg/kg) shows good efficacy in the human ovarian A2780, colon HCT-116, and pancreatic BX-PC3 carcinoma xenograft models.

ZLN024 Hcl is a novel AMPK allosteric activator; activated α1β1γ1 and α2β1γ1 by around 2–2.5 fold with an EC50 of about 1–2 uM.IC50 value: 1-2 uM (EC50) [1]Target: AMPK activatorZLN024 activated AMPK in L6 myotubes and stimulated glucose uptake and fatty acid oxidation without increasing the ADP/ATP ratio. ZLN024 also activated AMPK in primary hepatocytes, decreased fatty acid synthesis and glucose output. Treatment of db/db mice with 15 mg/kg/day ZLN024 improved glucose tolerance; liver tissue weight, triacylglycerol and the total cholesterol content were decreased. The hepatic transcriptional level of G6Pase, FAS and mtGPAT were reduced.

AZD-7762 is a potent ATP-competitive checkpoint kinase (Chk) inhibitor in with IC50 of 5 nM for Chk1.MLN1117 (INK1117) is a selective p110α inhibitor with IC50 of 15 nM.IC50 value: 15 nMTarget: p110αin vitro: MLN1117 also inhibits p110β (IC50=4.5μM), p110γ (IC50=1.9μM), p110δ (IC50=13.39μM), and mTOR (IC50=1.67μM). MLN1117 inhibits AKT phosphorylation and growth in PIK3CA mutant breast cancer cells with IC50 values around 2 μM, yet has no effect on cells lacking PTEN. GDC-0941 has similar effects on cell lines with PI3KCA mutation or PTEN loss. BCR-stimulated B cells treated with 1 μM A66 or MLN1117 displayed a significant reduction (up to 50%) in the magnitude of the phosphorylated AKT (pAKT) signal measured by intracellular flow cytometry. The effect of MLN1117 was dose-dependent. [3]

BML-277 is a selective checkpoint kinase 2 (Chk2) inhibitor with an IC50 of 15 nM.

CDK-IN-2 is a potent and specific CDK9 inhibitor with IC50 of <8 nM.IC50 Value: <8 nM [1]Target: CDK9In vitro:In vivo:CZC24832 is a selective inhibitor of PI 3-kinase γ (IC50 = 1.0 μM in a PI 3-Kγ-dependent fMLP-induced neutrophil migration assay); exhibits limited off-target effects in kinome profiling of 154 identified lipid and protein kinases and 922 other proteins.IC50 value: 1.0 uMTarget: PI 3Kγ

GSK180736A is a G protein-coupled receptor kinase 2 (GRK2) inhibitor with an IC50 of 0.77 μM.

MLN120B is a novel IKKβ inhibitor, used for cancer treatment.

Sanguinarine (chloride) is natural product.

VE-821 is a potent ATP-competitive inhibitor of ATR with Ki/IC50 of 13 nM/26 nM.

Brivanib is an ATP-competitive inhibitor against VEGFR2 with IC50 of 25 nM, abd has moderate potency against VEGFR-1 and FGFR-1, but > 240-fold against PDGFR-β.

SB 216763 is potent and selective glycogen synthase kinase-3 (GSK-3) inhibitor, with IC50 value of 34 nM.

AZD-5438 is a potent inhibitor of CDK1/2/9 with IC50 of 16 nM/6 nM/20 nM in cell-free assays. It also inhibits GSK3β, but is less potent to CDK5/6.CX-4945 sodium salt is an orally bioavailable, highly selective and potent CK2 inhibitor, with IC50 values of 1 nM against CK2α and CK2α'.

Src Inhibitor 1 is a potent and selective dual site Src tyrosine kinase inhibitor with IC50 values of 44 nM for Src and 88nM for Lck.

SB 203580 is a p38 MAPK inhibitor with IC50 of 0.3-0.5 μM, also blocks PKB phosphorylation with IC50 of 3-5 μM.

AZD1208 is a novel, orally bioavailable, highly selective PIM kinases inhibitor.

ZINC00881524 is a ROCK inhibitor.

AT9283 is a multi-targeted inhibitor with IC50s of 1.2 nM, 1.1 nM for JAK2 and JAK3, respectively, and is also potent to Aurora A, Aurora B and Abl(T315I).

GW2580 is a selective CSF-1R inhibitor for c-FMS with IC50 of 30 nM, and shows 150- to 500-fold selective compared to b-Raf, CDK4, c-KIT, c-SRC, EGFR, ERBB2/4, ERK2, FLT-3, GSK3, ITK, JAK2, etc.TCS PIM-1 1(sc-204330) is a potent and selective ATP-competitive Pim-1 kianse inhibitor with IC50 of 50 nM, displays good selectivity over Pim-2 and MEK1/MEK2(IC50s >20,000 nM).IC50 value: 50 nM [1]Target: Pim-1TCS PIM-1 1 bound convincingly within the ATP-binding site of Pim-1 suggesting an ATP-competitive inhibitory mechanism. Preliminary data further suggested that 1 lacked in vitro inhibitory activity toward related serine/threonine kinases Pim-2 and MEK1/2 (IC50 > 20 lM). Hence, small molecules similar to TCS PIM-1 1 may serve as useful starting scaffolds for the development of other improved yet selective Pim-1 inhibitors.

APTO-253 is a novel small molecule with potent anti-tumor activity in cancer cells via induction of the gene that expresses the Krüppel-like factor 4 (KLF4) master transcription factor, leading to cell cycle inhibition and programmed cell death.Target: p21in vitro: APTO-253 demonstrats potent and selective growth inhibition of a variety of solid tumor cell lines, including colon cancer, non-small cell lung cancer (NSCLC), prostate cancer and melanoma, with IC50 values of 0.04- 2.6 μM. APTO-253 demonstrats even great potency of growth inhibitory activity against leukemia cell lines, including AML, ALL and chronic myeloid leukemia (CML), as well as non-Hodgkin's lymphoma (NHL) cell lines, with IC50 values ranging from 7 nM - 0.3 μM.[1]in vivo: Nonclinical pharmacology studies have demonstrated that APTO-253 exerts in vivoanti-tumor activity in solid tumors and hematologic cancers. [1]

LJI308 is a new and potent pan-RSK inhibitor, with IC50 of 6 nM, 4 nM, and 13 nM for RSK1, RSK2, and RSK3, respectively.IC50 value: 6/4/13 nMTarget: RSK1/2/3in vitro: LJI308 efficiently inhibits RSK activity. LJI308 inhibites S6K1 with an IC50 of 0.8 μM, representing a 200-fold lower inhibition than that of RSK2. LJI308 inhibits MEK4 less than 50% at 10 μMand HIP kinase 1 less than 50% at 1 μM. [1] LJI308 inhibits the growth and survival of TNBC. LJI308 also suppresses the growth of HTRY-LT cells in 3-dimensional soft agar cultures. LJI308 is one of the first potent and effective targeted therapies for TNBC that, unlike currently utilized drugs, exhibits efficacy in eliminating the CSC population. [2]

SB 239063 is a potent and selective p38 MAPK inhibitor (IC50 = 44 nM for p38α). SB 239063 displays > 220-fold selectivity over ERK, JNK1 and other kinases; ~ 3-fold more selective than SB 203580. IC50 value: 44 nM ( p38α)Target: p38 MAPKSB 239063 reduces inflammatory cytokine production and is neuroprotective following oral administration in vivo.

PD168393 is an potent, cell-permeable, irreversible EGFR inhibitor with IC50 of 0.70 nM, irreversibly alkylate Cys-773, inactive against insulin, PDGFR, FGFR and PKC. target: EGFRIC 50: 0.7 nM [1](1) PD 168393 inhibite EGFr autophosphorylation in A431 human epidermoid carcinoma cells with >9-fold greater potency than PD 174265.[1](2) PD 168393 decrease the production of TNF-α and phosphrylation of ERK1/2 and p38 induced by LPS in cardiomyocytes.[2](3) PD168393 completely inhibits AKT and ERK phosphorylation at concentrations as low as 0.03 umol/L.[3](4) PD168393 could induce apoptosis and inhibit cell growth in ErbB2 positive lung and breast cancer cell lines.[3](5) PD168393 disrupted MEK1/p44/42 ERK signaling in HaCaT cells as determined by inhibition of phospho-p44/42 ERK. [4]

Tivantinib is a novel and highly selective c-Met tyrosine kinase inhibitor with Ki of 355 nM.MSDC 0160 act as an insulin sensitizer and a modulator of mitochondrial pyruvate carrier (MPC), a key controller of cellular metabolism that influences mTOR (mammalian target of rapamycin) activation. In Vitro: MSDC-0160 acts as insulin sensitizers without activating PPARγ. MSDC-0160 (10 μM) pretreatment (1 hour) prevents the MPP+ (10 μM)-induced loss of both tyrosine hydroxylase (TH)-immunoreactive differentiated Lund human mesencephalic (LUHMES) cells. MSDC-0160 protects only TH-immunoreactive neurons, which is consistent with the selected concentration of MPP+ primarily being toxic to dopamine neurons. In addition, MSDC-0160 counteracts both MPP+-induced shortening of neurite length and reduces branching in both LUHMES cells. MSDC-0160 (10 or 100 μM) prevents the loss of GFP-fluorescent dopaminergic neurons induced by MPP+ (0.75 mM) in nematodes (P =0.0001), whereas 1 μM MSDC-0160 does not. MSDC-0160 (10 μM) blocks LPS-induced increases in iNOS expression in BV2 cell lysates. MSDC-0160 is mainly to prevent the activation of mTOR produced by the metabolic changes rather than to directly inhibit mTOR kinase activity[1]. PPARγ sparing TZD, MSDC-0160, reduces resistance in the insulin/IGF-1 signaling pathway and restores IGF-1-induced akt phosphorylation. MSDC-0160 (10-20 μM) in conbination with IGF-1 prevents the loss of insulin content and maintains insulin secretion. Treatment of human islets with MSDC-0160 (1-50 μM) activates AMPK and downregulates mTOR. MSDC-0160 (1-50 μM) treatment maintains human β-cell phenotype[2]. The combined treatment with PPARγ ligands (MSDC 0160) and γ-radiation synergistically induces caspase-dependent apoptotic cell death, and PPARγ ligands significantly enhance the γ-radiation-induced DNA damage response in a PPARγ-independent manner[3].

In Vivo: MSDC-0160 (30 mg/kg per day, p.o.) can be observed in plasma and brain tissue of the mice, proving MSDC-0160 can effectively enter the brain. MSDC-0160 (30 mg/kg per day, p.o.) treatment 3 days after MPTP injection, improves motor behavior, protects nigrostriatal neurons, and suppresses disease progression in the MPTP mouse model of Parkinson’s disease (PD), improves motor behavior in the open-field and rotarod tests in the En1+/- genetic mouse model of PD, and prevents dopaminergic neurodegeneration in the En1+/- genetic mouse model of PD. MSDC-0160 (30 mg/kg, p.o.) modulates mTOR signaling in C. elegans and the MPTP mouse model of PD. MSDC-0160 down-regulates mTOR signaling and restores autophagy in the En1+/- genetic mouse model of PD[1].

LDC000067 is a highly specific CDK9 inhibitor with an IC50 value of 44±10 nM in vitro.AIM-100 is a small molecule inhibitor of Ack1 with an IC50 of 24 nM.IC50 value: 24 nM [3]Target: Ack1Ack1 inhibitor AIM-100 not only inhibited Ack1 activation but also suppressed AKT tyrosine phosphorylation, leading to cell cycle arrest in the G1 phase [1].The Ack1 inhibitor AIM-100 not only inhibited Ack1 activity but also was able to suppress AR Tyr(267) phosphorylation and its recruitment to the ATM enhancer. Notably, AIM-100 suppressed Ack1 mediated ATM expression and mitigated the growth of radioresistant CRPC tumors [2]. AIM-100, not only inhibited Ack1 activation but also able to suppress pTyr267-AR phosphorylation, binding of AR to PSA, NKX3.1, and TMPRSS2 promoters, and inhibit AR transcription activity [3].

SU 6656 is a selective inhibitor of Src kinases, Including Src, Yes, Lyn, and Fyn (IC50 = 280, 20, 130, 170 nM, respectively).IC50 value: Target: Src kinases inhibitorin vitro: By comparing PDGF-stimulated tyrosine phosphorylation events in untreated and SU6656-treated cells, we found that some substrates (for example, c-Cbl, and protein kinase C delta) were Src family substrates whereas others (for example, phospholipase C-gamma) were not [1]. Selective inhibition of SFKs with SU6656 delocalized E-cadherin and disrupted cellular junctions without affecting E-cadherin expression and this effect was phenocopied by knockdown of Src or Yes [2]. Inhibiting Src kinase activity by SU6656 suppressed TGFβ-induced RhoA and ATF2 activation but not Smad2 phosphorylation [3]. SU6656, the selective inhibitor of the Src kinase activity, decreased up-regulation of the mTORC1 signalling and moreover, unlike rapamycin, it did not induce the activation of Akt/PKB and its downstream targets in HBL melanoma cells [4].in vivo: Ischemic postconditioning induced neuroprotective effects were significantly attenuated by pre-treatment of selective Src Kinase inhibitors SU-6656 (4 mg/kg i.p.) and PP1 (0.2 mg/kg i.p.) [5]. SU6656 and SKI-606 (bosutinib) enhanced immunotoxin killing of mesothelin-expressing cells by SS1P and CD22-expressing cells by HA22 (moxetumomab pasudotox). SU6656 also enhanced the antitumor effects of SS1P and HA22 in mouse xenograft tumor models [6].

PF-04217903 is a selective ATP-competitive c-Met inhibitor with IC50 of 4.8 nM, susceptible to oncogenic mutations (no activity to Y1230C mutant).IC50 value: 4.8 nM [1]Target: in vitro: Being more selective than staurosporine or PF-02341066, PF-04217903 displays >1000-fold selectivity for c-Met over a panel of 208 kinases, although more susceptible to oncogenic mutations of c-Met that attenuate potency than PF-02341066. In addition to WT c-Met, PF-04217903 displays similar potency to inhibit the activity of c-Met-H1094R, c-Met-R988C, and c-Met-T1010I with IC50 of 3.1 nM, 6.4 nM, and 6.7 nM, respectively, but has no inhibitory activity against c-Met-Y1230C with IC50 of >10 μM [1]. PF-04217903 in combination with sunitinib significantly inhibits endothelial cells, but not the tumor cells B16F1, Tib6, EL4, and LLC [2] PF-04217903 significantly inhibits the clonogenic growth of LXFA 526L and LXFA 1647L with IC50 values of 16 nM, and 13 nM, respectively, yielding an additive effect when in combination with cetuximab [3]. in vivo: Although unable to inhibit tumor growth in the sunitinib-sensitive B16F1 and Tib6 tumor models, the combination of PF-04217903 and sunitinib significantly inhibits tumor growth in sunitinib-resistant EL4, and LLC tumor models compared with sunitinib or PF-04217903 alone by significantly blocking vascular expansion, indicating a functional role for HGF/c-Met axis in the sunitinib-resistant tumors [2].

Tetrahydrocurcumin is one of the major metabolites of Curcumin; apoptosis inducer and has been demonstrated to be an antioxidant.IC50 value:Target:in vitro: HC exhibited significant cell growth inhibition by inducing MCF-7 cells to undergo mitochondrial apoptosis and G2/M arrest. Moreover, co-treatment of MCF-7 cells with THC and p38 MAPK inhibitor, SB203580, effectively reversed the dissipation in mitochondrial membrane potential (Δψm), and blocked THC-mediated Bax up-regulation, Bcl-2 down-regulation, caspase-3 activation as well as p21 up-regulation, suggesting p38 MAPK might mediate THC-induced apoptosis and G2/M arrest [1]. THC is superior to curcumin for induction of GSH peroxidase, glutathione-S-transferase, NADPH: quinone reductase, and quenching of free radicals [2]. in vivo: THU was administered intragastrically at dose of 50 or 100 mg/kg/day concurrently with Cd treatment. Supplementation with THU significantly decreased blood pressure, improved vascular responsiveness, and reversed the structural and mechanical alterations of the aortas, including collagen and elastin deposition [3]. brain edema and Evans Blue leakage were reduced in I/R + THC-treated groups as compared to sham-operated groups along with reduced brain infarct size. THC also decreased oxidative damage and ameliorated the homocysteinylation of cyto-c in-part by MMP-9 activation which leads to autophagy in I/R groups as compared to sham-operated groups [4].

SB1317 is a potent inhibitor of CDK2, JAK2, and FLT3 for the treatment of cancer, with IC50 of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively.

TEPP-46 is a potent and selective activator of recombinant pyruvate kinase M2 (PKM2) with half-maximum activating concentration (AC50 value) of 92 nM, and has little or no effect on PKM1, PKL and PKR.

CC-115 hydrochloride is a inhibitor of mTOR/DNA-PK (IC50= 21/ 13 nM).IC50 value: 21 nM (for mTOR), 13 nM (for DNA-PK)Target: mTOR, DNA-PKin vitro: The IC50 values for CC-115 are >10 μM against a panel of CYP enzymes and >33 μM for the hERG ion channel. When screened in a single point assay at 10 μM against a Cerep receptor and enzyme panel only one target was inhibited >50% (PDE3, IC50 = 0.63 μM). in vivo: CC-115 shows good PK profiles across multiple species with 53%, 76%, and 100% oral bioavailability in mouse, rat, and dog, respectively. CC-115, with favorable physicochemical and pharmacokinetic properties, demonstrates mTOR pathway inhibition and tumor growth inhibition, as well as a good safety profile, suitable for clinical development.Motesanib is a potent ATP-competitive inhibitor of VEGFR1/2/3 with IC50s of 2 nM/3 nM/6 nM, respectively, and has similar activity against Kit, and is appr 10-fold more selective for VEGFR than PDGFR and Ret.

GNF-2 is a highly selective non-ATP competitive inhibitor of oncogenic Bcr-Abl activity (IC50 = 0.14 μM).IC50 value: 0.14 uM [1]Target: Bcr-Ablin vitro: Ba/F3 cells harboring native or T315I mutated Bcr-Abl constructs were treated with GNF-2 and AKIs. We monitored the effect of GNF-2 with AKIs on the proliferation and clonigenicity of the different Ba/F3 cells. In addition, we monitored the auto-phosphorylation activity of Bcr-Abl and JAK2 in cells treated with GNF-2 and AKIs [2]. GNF-2 increased the effects of AKIs on unmutated BCR/ABL. Interestingly, the combination of Dasatinib and GNF-2 overcame resistance of BCR/ABL-T315I in all models used in a synergistic manner [3].GNF-2 dose-dependently inhibited the proliferation of osteoclast precursors through the suppression of the M-CSFR c-Fms. In addition, GNF-2 accelerated osteoclast apoptosis by inducing caspase-3 and Bim expression. Furthermore, GNF-2 interfered with actin cytoskeletal organization and subsequently blocked the bone-resorbing activity of mature osteoclasts [4].in vivo: Combining PDMP and GNF-2 eliminated transplanted-CML-T315I-mutants in vivo and dose dependently sensitized primary cells from CML T315I patients to GNF-2-induced proliferation inhibition and apoptosis[5].

Linifanib (ABT-869; AL-39324) is a novel, potent ATP-competitive VEGFR/PDGFR inhibitor for KDR, CSF-1R, Flt-1/3 and PDGFRβ with IC50 of 4 nM, 3 nM, 3 nM/4 nM and 66 nM respectively.IC50 value: 4 nM/3 nM/3 nM/4 nM /66 nM(KDR/CSF-1R/Flt-1/Flt-3PDGFRβ) [1]Target: VEGFR/PDGFRin vitro: Linifanib shows inhibitory to Kit, PDGFRβ and Flt4 with IC50 of 14 nM, 66 nM and 190 nM in kinases assay. Linifanib also inhibits ligand-induced KDR, PDGFRβ, Kit, and CSF-1R phosphorylation with IC50 of 2 nM, 2 nM, 31 nM and 10 nM at cellular level and this cellular potency could be affected by serum protein. Linifanib suppresses VEGF-stimulated HUAEC proliferation with IC50 of 0.2 nM. While Linifanib has weak activity against tumor cells which are not induced by VEGF or PDGF, except for MV4-11 leukemia cells (with constitutively active form of Flt3) with IC50 of 4 nM. Linifanib could cause a decrease in S and G2-M phases with a corresponding increase in the sub-G0-G1 apoptotic population in MV4-11 cells [1]. Linifanib binds to the ATP-binding site of CSF-1R with Ki of 3 nM [2]. Linifanib (10 nM) exhibits a reduced phosphorylation of Akt at Ser473 and decreased phosphorylation of GSK3βat Ser9 in Ba/F3 FLT3 ITD cell lines [3]. in vivo: Linifanib (0.3 mg/kg) results in complete inhibition of KDR phosphorylation in lung tissue. Linifanib also inhibits the edema response with ED50 of 0.5 mg/kg. Linifanib (7.5 and 15 mg/kg, bid) significantly inhibits both bFGF- and VEGF-induced angiogenesis in the cornea. Linifanib inhibits tumor growth in flank xenograft models including HT1080, H526, MX-1 and DLD-1 with ED75 from 4.5-12 mg/kg. Linifanib also shows efficacy in A431 and MV4-11 xenografts at low dose levels. Linifanib (12.5 mg/kg bid) reveals a decrease of microvasculure density in MDA-231 xenograft. Linifanib shows a Cmax and AUC24 hours with 0.4 μg/mL and 2.7 μg·hour/mL in HT1080 fibrosarcoma model [1].

WHI-P154 is a potent JAK3 inhibitor with IC50 of 1.8 μM, no activity against JAK1 or JAK2, also inhibits EGFR, Src, Abl, VEGFR and MAPK, prevents Stat3, but not Stat5 phosphorylation.IC50 Value: 1.8 uM (JAK3); 4 nM(EGFR);100 nM(VEGFR) [1]Target: JAK3; VEGFR/EGFRin vitro: WHI-P154 is first described as a JAK3 inhibitor that displays no activity at JAK1 or JAK2. WHI-P154 inhibits STAT1 activation, iNOS expression and NO production in macrophages in vitro. But it is proved that WHI-P154 also inhibits other common kinases including EGFR, Src, Abl, VEGFR, MAPK and PI3-K and induces apoptosis in human glioblastoma cell lines [1]. inhibitor WHI-P154 decreased IFN-gamma-induced nuclear levels of signal transducer and activator of transcription 1alpha (STAT1alpha). JAK inhibitor WHI-P154 decreased also iNOS protein and mRNA expression and NO production in a concentration-dependent manner [2]. WHI-P154) exhibited significant cytotoxicity against U373 and U87 human glioblastoma cell lines, causing apoptotic cell death at micromolar concentrations. In vitro treatment with EGF-P154 resulted in killing of glioblastoma cells at nanomolar concentrations with an IC50 of 813 +/- 139 nM, whereas no cytotoxicity against EGF-R-negative leukemia cells was observed, even at concentrations as high as 100 microM [3].in vivo: The in vivo administration of EGF-P154 resulted in delayed tumor progression and improved tumor-free survival in a severe combined immunodeficient mouse glioblastoma xenograft model. Whereas none of the control mice remained alive tumor-free beyond 33 days (median tumor-free survival, 19 days) and all control mice had tumors that rapidly progressed to reach an average size of > 500 mm3 by 58 days, 40% of mice treated for 10 consecutive days with 1 mg/kg/day EGF-P154 remained alive and free of detectable tumors for more than 58 days with a median tumor-free survival of 40 days. The tumors developing in the remaining 60% of the mice never reached a size > 50 mm3 [3].

JNJ-38877605 is an ATP-competitive inhibitor of c-Met with IC50 of 4 nM, 600-fold selective for c-Met than 200 other tyrosine and serine-threonine kinases.IC50 value: 4 nM [1]Target: c-Metin vitro: JNJ-38877605 shows more than 600-fold selectivity for c-Met compared with more than 200 other diverse tyrosine and serine-threonine kinases and also potently inhibits HGF-stimulated and constitutively activated c-Met phosphorylation in vitro. [1] In EBC1, GTL16, NCI-H1993, and MKN45 cells, JNJ-38877605 (500 nM) leads to a significant reduction of phosphorylation of Met and RON, another key player in invasive growth [2]. A recent study shows that JNJ-38877605 is involved in modulating secretion of IL-8, GROa, uPAR and IL-6 in GTL16 cells [3]. in vivo: In mice bearing established GTL16 xenografts, JNJ-38877605, dosed orally with 40 mg/kg/day for 72 hours, results in a statistically significant decrease in the plasma levels of human IL-8 (from 0.150 ng/mL to 0.050 ng/mL) and GROα (from 0.080 ng/mL to 0.030 ng/mL). While concentrations of uPAR in the blood become reduced to more than 50% at the same dose [3].

IM-12 is a potent GSK-3β inhibitor with IC50 of 53 nM; shows a significant activity in several biological tests which was comparable or even outplayed the effects of the known SB-216763.IC50 value: 53 nM [1]Target: GSK-3β inhibitorIM-12 acts as GSK-3b inhibitor resulting in the activation of downstream components of canonical Wnt signalling and has an adjacent positive impact on the neuronal differentiation in human neural progenitor cells [1].

CH5132799 selectively inhibits class I PI3Ks, such as PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ with IC50 values of 0.014, 0.12, 0.50, and 0.36 uM, respectively; shows less inhibition of class II PI3Ks, class III PI3ks, and mTOR.IC50 value: 14/120/500/360 nM (PI3Kα/β/δ/γ) Target: Prediction of CH5132799 response on the basis of PIK3CA mutations could enable patient stratification in clinical settings. CH5132799 exhibited a strong inhibitory activity especially against PI3Kα (IC(50)=0.014 μM). In human tumor cell lines with PI3K pathway activation, CH5132799 showed potent antiproliferative activity. CH5132799 is orally available and showed significant antitumor activity in PI3K pathway-activated human cancer xenograft models in mice. Cancer cell lines harboring PIK3CA mutations are significantly sensitive to CH5132799. In human tumor cell lines with PI3K pathway activation by mutation, CH5132799 shows potent antiproliferative activity [HCT116(CRC): IC50 = 0.20 lM, KPL-4(BC):13 IC50 = 0.032 lM, T-47D(BC): IC50 = 0.056 lM, SK-OV-3(Ovarian): IC50 = 0.12 lM].

Ro 28-1675 (Ro 0281675) is a potent allosteric GK activator with a SC1.5 value of 0.24± 0.0019 uM. IC50 value: 0.24± 0.0019 uM (SC1.5) [1]Target: Glucokinase activatorThe R stereoisomer Ro 28-1675 activated GK with a SC1.5 of 0.24 uM, while the S isomer did not activated GK up to 10 uM. Oral administration of Ro 28-1675 (50 mg/Kg) to male C57B1/6J mice caused a statistically significant reduction in fasting glucose levels and improvement in glucose tolerance relative to the vehicle treated animals [1]. Comparison of rat PK parameters indicated that Ro 28-1675 displayed lower clearance and higher oral bioavailability compared to 9a. Following a single oral dose, Ro 28-1675 reduced fasting and postprandial glucose levels following an OGTT, was well tolerated, and displayed no adverse effects related to drug administration other than hypoglycemia at the maximum dose (400 mg). [1]

CCT245737 is a potent, ATP-competitive CHK1 inhibitor with an IC50 of 30-220 nM.target:CHK1;IC 50: 30-220nM;In vitro: CCT245737 shows <50% inhibition at 10 μM for 85/121 kinases, representing a selectivity for CHK1 inhibition of >5000-fold over these enzymes. [1] CCT245737 enhanced gemcitabine antitumor activity to a greater degree than for higher doses of either agent alone, without increasing toxicity. [2]In vivo: CCT2457374 shows an increase in plasma and tumoconcentrations between 3-100 mg/kg po. [1]

BI 78D3 is a competitive c-Jun N-terminal kinase (JNK) inhibitor with IC50 of 280 nM that displays > 100 fold selectivity over p38α and no activity at mTOR and PI-3K.target: JNKIC 50: 280 nM1) BI 78D3 Inhibits JNK interacting protein 1 (JIP1)-JNK binding (IC50= 500 nM) and prevents JNK substrate phosphorylation. 2) I-78D3 not only blocks JNK dependent Con A-induced liver damage but also restores insulin sensitivity in mouse models of type 2 diabetes.3) The reference for animal administration is 25 mg/kg

PF-4989216 is a novel potent and selective PI3K inhibitor. PF-4989216 inhibits PI3Kalpha (Ki=0.6 nM) and mTOR (Ki=1440 nM).IC50 value: 0.6 nM (Ki, PI3Kalpha), 1440 nM (Ki, mTOR) [1]Target: PI3Kin vitro: PF-4989216inhibits pAKT-S473 with IC50 of 79 nM. [1] PF-4989216 is a potent inhibitor of pan-PI3K isoforms and demonstrates excellent selectivity when screened against more than 100 kinases and 50 non-kinases. PF-4989216 is significantly more potent in SCLCs with PIK3CA mutations than wild-type lines, including cells with PIK3CA copy number gain, providing evidence that SCLCs harboring PIK3CA mutations are more sensitive to inhibition by PF-4989216. [2]vivo: PF-4989216 exhibits good exposure in mice after oral administration and the unbound drug concentration increased with dose, with the ability to maintain approximately 700, 1,900, and 2,100 nM at the 7-hour time point at dosages of 50, 150, and 350 mg/kg, respectively. [2]SNS-032 is a selective inhibitor of cyclin-dependent kinase (CDK), inhibiting CDK2/7/9 with IC50s of 48 nM/62 nM/4 nM.

CL-387785(EKI785; WAY-EKI 785) is an irreversible inhibitor of EGFR with IC50 of 370+/-120 pM; is able to overcome resistance caused by the T790M mutation on a functional level.IC50 value: 370+/-120 pMTarget: EGFRin vitro: CL-387785 blocked EGF-stimulated autophosphorylation of the receptor in cells (ic50 approximately 5 nM), inhibited cell proliferation (IC50 = 31-125 nM) primarily in a cytostatic manner in cell lines that overexpress EGF-R or c-erbB-2 [1]. Whereas transformation by most EGFR mutants confers on cells sensitivity to erlotinib and gefitinib, transformation by an exon 20 insertion makes cells resistant to these inhibitors but more sensitive to the irreversible inhibitor CL-387,785 [3]. CL-387,785 is able to overcome resistance caused by the T790M mutation on a functional level, correlating with effective inhibition of downstream signaling pathways [4].in vivo: CL-387785 profoundly blocked the growth of a tumor that overexpresses EGF-R in nude mice (when given orally at 80 mg/kg/day for 10 days, daily) [1]. Treatment of BPK mice with EKI-785 resulted in a marked reduction of collecting tubule (CT) cystic lesions, improved renal function, decreased biliary epithelial abnormalities, and an increased life span. Cystic animals treated with EKI-785 to postnatal day 48 (P-48) were alive and well with normal renal function, a reduced CT cystic index of 2.0 (P < 0.02), a threefold increased in maximum urinary concentrating ability (P < 0.01), and a significant decrease in biliary epithelial proliferation/fibrosis (P < 0.01) [2].

LJH685 is a potent , specific and selective RSK inhibitor, inhibits RSK1, 2, and 3 biochemical activities with IC50 of 4 to 13 nM.IC50 value: 4 to 13 nM [1]Target: RSKin vitro: LJH685 efficiently inhibits RSK activity in cells. LJH685 RSK inhibition correlates with antiproliferative effects in MAPK pathway-dependent cancer cell lines only in anchorage-independent growth setting. The EC 50 values of LJH685 is 0.73 and 0.79 μM in MDA-MB-231 and H358. [1]

GSK 650394 is a novel SGK inhibitor with IC50 of 62 nM and 103 nM for SGK1 and SGK2 in the SPA assay respectively.

Losmapimod is a selective, potent, and orally active p38 MAPK inhibitor with pKi of 8.1 and 7.6 for p38α and p38β, respectively.

Acumapimod (BCT197) is an orally active p38 MAP kinase inhibitor, with an IC50 of less than 1 μM for p38α.

T56-LIMKi is a selective inhibitor of LIMK2; inhibits the growth of Panc-1 cells with an IC50 of 35.2 μM.

PIK-93 is the first potent, synthetic PI4K (PI4KIIIβ) inhibitor with IC50 of 19 nM, and also inhibits PI3Kα with IC50 of 39 nM.

5-Iodotubercidin is a potent adenosine kinase inhibitor with IC50 of 26 nM.

Dovitinib is a multitargeted RTK inhibitor, and inhibits FGFR3 with IC50 of 5 nM.

Erlotinib inhibits purified EGFR kinase with an IC50 of 2 nM.Reversine is a novel class of ATP-competitive Aurora kinase inhibitor with IC50s of 400, 500 and 400 nM for Aurora A, B and C, respectively.

PD166866 is a selective FGFR tyrosine kinase inhibitor with an IC50 of 52.4 nM.

IRAK inhibitor 6 is an inhibitor of interleukin-1 receptor associated kinase 4 (IRAK-4) with IC50 of 160 nM.Dinaciclib is a potent and selective inhibitor of CDKs, with IC50s of of 1, 1, 3, and 4 nM for CDK2, CDK5, CDK1, and CDK9 activity, respectively.

IC-87114 was the first isoform-selective PI3K inhibitor. p110δ(IC50 = 0.13 μM) vs. p110α(IC50 = 200 μM), p110β(IC50 = 16 μM) and p110γ(IC50 = 61 μM).D4476 is a potent, selective and cell-permeable inhibitor of casein kinase 1(CK1) with an IC50 value of 0.3 μM in vitro.GSK583 is a highly potent and selective inhibitor of RIP2 Kinase, with IC50 of 5 nM.Sunitinib is a potent tyrosine kinase inhibitor targeting VEGFR2 and PDGFRβ with IC50 of 80 nM and 2 nM, respectively.

PLX647 is a highly specific dual FMS/KIT kinase inhibitor with IC50 of 28/16 nM respectively.IC50 value: 28/16 nM(FMS/KIT) [1]Target: FMS/KIT dual inhibitorin vitro: PLX647 was tested against a panel of 400 kinases at a concentration of 1 μM, 35-fold above its FMS enzymatic IC50 and 60-fold above its KIT enzymatic IC50. In addition to FMS and KIT, the activities of only nine kinases were inhibited by more than 50%. PLX647 potently inhibits the growth of FLT3–ITD-expressing MV4-11 cells (IC50 = 0.11 μM) but not OCI-AML5 (IC50 = 1.6 μM), which express wild-type FLT3. PLX647 displayed minimal inhibition of the proliferation of Ba/F3 cells expressing BCR–KDR (IC50 = 5 μM) [1]. in vivo: PLX647 (40 mg/kg) was dosed orally 4.25 h before LPS injection. Treatment with PLX647 reduced serum TNF-α levels by 85% compared with the vehicle control. In the same experiment, the positive control dexamethasone (0.5 mg/kg, PO) lowered the TNF-α levels by 96%. Treatment with 40 mg/kg PLX647 also resulted in significant inhibition of IL-6 release (75%), with similar potency to dexamethasone (70%) . In the UUO kidneys, treatment with PLX647 [40 mg/kg twice daily (BID)] resulted in reduction in the levels of F4/80+ macrophages by 77% compared with vehicle [1].

EAI045 is an allosteric inhibitor that targets selected drug-resistant EGFR mutants.target: EGFR [1]In vitro: EAI045 potently inhibit EGFR Y1173 phosphorylation in H1975 cells. ( EC50: 2 nM ). [1] EAI045 represents a novel selective inhibitor that can overcome T790M and C797S resistance mutations. [2]In vivo: EAI045 in combination with cetuximab is effective in mouse models of lung cancer driven by EGFR(L858R/T790M) and by EGFR(L858R/T790M/C797S), a mutant that is resistant to all currently available EGFR TKIs. EAI045 revealed a maximal plasma concentration of 0.57 μM, a half-life of 2.15 h, and oral bioavailability of 26% after dosing at 20 mg/kg.[1] EAI045 markedly reduced tumor growth in a mouse model of L858R/T790M. [2]IMD-0354 is a synthetic selective NF-kB inhibitor.Target: IKK β (IKK-2)in vitro: IMD-0354 inhibits p65 translocation to the nucleus promoted by FGF2 in PASMCs. Furthermore, the time courses of Erk1/2, MCP-1, and PAI-1 stimulated with FGF2 are each markedly shortened by IMD-0354. IMD-0354 suppresses proliferation and induced apoptosis of PASMCs. IMD-0354 decreases FGF2, PAI-1, t-PA mRNA expressions. IMD-0354 also inhibits the translocation of NF-kB subunit p65 into the nucleus.in vivo: IMD-0354 has potential as a new therapeutic tool for PAH. IMD-0354 improves survival in the PAH rats. IMD-0354 improves physical signs of RVH in the PAH rats. IMD-0354 also decreases medial hypertrophy in the pulmonary arterioles.Chelerythrine Chloride is a potent, cell-permeable inhibitor of protein kinase C and mitogen-activated protein kinase (MAPK), with IC50 of 660 nM for PKC, competitive with respect to the phosphate acceptor and non-competitive with respect to ATP.WP1130 inhibits the autoactivation of Bcr-Abl by inducing its rapid down-regulation with IC50 of 1.8 μM. WP1130 also is a deubiquitinase inhibitor.

PI-103 hydrochloride is a potent PI3K/Akt and mTOR inhibitor with IC50 values of 2 nM for recombinant PI3K isoform p110α and 30 nM for mTOR.K145 is a selective SphK2 inhibitor with an IC50 of 4.30±0.06 μM , while no inhibition of SphK1 at concentrations up to 10 μM.IC50 value: 4.3 uM [1]Target: SphK2in vitro: K145 inhibited the activity of SphK2 in a dose-dependent manner with an IC50 of 4.30±0.06 uM , while no inhibition of SphK1 at concentrations up to 10 uM was observed. Lineweaver-Burk analysis revealed a Ki of 6.4±0.7 uM for SphK2 and indicated that K145 is a substrate competitive inhibitor (with sphingosine). K145 accumulates in U937 cells, suppresses the S1P level, and inhibits SphK2. K145 also exhibited inhibitory effects on the growth of U937 cells as well as apoptotic effects in U937 cells, and that these effects may be through the inhibition of down-stream ERK and Akt signaling pathways [1].in vivo: K145 also significantly inhibited the growth of U937 tumors in nude mice by both intraperitoneal and oral administration, thus demonstrating its in vivo efficacy as a potential lead anticancer agent [2].

AMG319 is a potent and selective PI3Kδ inhibitor with IC50 of 18 nM, also inhibits PI3Kγ with IC50 of 850 nM.IC50: 18 nM (PI3Kδ), 850 nM (PI3Kγ), 2.7μM (PI3Kβ), 33 μM (PI3Kα)Target: PI3KIn vitro: AMG319 is a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation. AMG319 inhibits anti-IgM/CD40L-induced B cell proliferation with IC50 of 8.6 nM and reduces pAkt level with IC50 of 1.5 nM. AMG319 also inhibits anti-IgD-induce CD-69 expression in HWB.[1]In vivo: In female Lewis rats, AMG319 (3 mg/kg, p.o.) inhibits the KLH-induced inflammatory response by 88%. In the transgenic (IgMm) mice, AMG319 (, p.o.) inhibits in vivo pAKT with IC50 of 1.9 nM.[1]

TIC10 isomer is an isomer of TIC10. TIC10 is a potent, orally active, and stable TRAIL inducer, also inhibits Akt and ERK activity.TIC10 is a potent, orally active, and stable TRAIL inducer, also inhibits Akt and ERK activity.

APS-2-79 is an antagonist of MEK phosphorylation by RAF through direct binding of the KSR active site.BIBX 1382 is a potent, selective inhibitor of EGFR tyrosine kinase (IC50 = 3 nM); displays > 1000-fold lower potency against ErbB2 (IC50 = 3.4 μM) and a range of other related tyrosine kinases (IC50 > 10 μM). IC50 value: 3 nM [1]Target: EGFRin vitro: BIBX1382 and BIBU1361 are both potent and selective submicromolar inhibitors of the EGFR kinase activity. An IC50 value of 3 nM was determined for both compounds. The potency of these two compounds compares with the one obtained with Iressa, which is a leading EGFR inhibitor in the field. Inhibition of the closest family member, HER2, was 100- to 1000-fold less potent. Furthermore, BIBX1382 and BIBU1361 did not inhibit a number of other related tyrosine kinases [1].in vivo: In nude mice, oral once daily dosing at 10 mg/kg with either BIBX1382 or BIBU1361 completely suppressed tumor growth of human A431 xenografts with respective T/C values of 15 and 6% after 2 weeks of treatment [1].

CPDA is a novel potent SHIP2 inhibitor that can effectively ameliorate insulin resistance in 3T3-L1 adipocytes.Target: SHIP2in vitro: CPDA was found to enhance insulin signaling.in vivo: CPDA greatly improves abnormal glucose metabolism in diabetic animals. CPDA was also found to improve the abnormal glucose metabolism in db/db mice.

Purvalanol A(NG-60) is a potent, cell-permeable, and selective inhibitor of cyclin-dependent kinases (CDKs) with IC50 values of 4, 70, 35, 850, and 75 nM for cdc2/cyclin B, Cdk2/cyclin A, Cdk2/cyclin E, Cdk4/cyclin D1 and Cdk5-p35, respectively.IC50 value: [1] [2]Target: CDKs inhibitorin vitro: Purvalanol A reversibly arrests synchronized cells in the G1 and G2 phase of the cell cycle, inhibiting both cell proliferation and cell death [3]. At 10 μM, purvalanol A potently suppresses the anchorage-independent growth of c-Src-transformed cells as well as HT29 and SW48 human colon cancer cells [4].

ZM 336372 is a potent and selective c-Raf inhibitor with IC50 of 70 nM, 10-fold selectivity over B-RAF, no inhibition to PKA/B/C, AMPK, p70S6, etc.IC50 value: 70 nM [1]Target: c-Rafin vitro: ZM 336372 shows 10-fold selectivity over B-Raf. ZM 336372 weakly inhibits SAPK2a/p38α and SAPK2b/p38β with IC50 of 2 μM, and is selective over 17 other protein kinases including PKA, PKC, AMPK, p42 MAPK, MKK1, SAPK1/JNK, and CDK1 even at the concentration of up to 50 μM. ZM 336372 does not prevent constitutive as well as growth factor or phorbol ester induced activation of MKKl or p42 MAPK/ERK2. Moreover, ZM 336372 dose not reverse the phenotype of Ras- or Raf-transformed cell lines. ZM 336372 treatment induces >100 activation of c-Raf and the B-Raf isoform, but it does not trigger any activation of MKKI or p42 MAPK/ERKP or induce any increase in the GTP-loading of Ras, suggesting that a feedback control loop exists by which Raf isoforms suppress their own activation, such that inhibition is always counterbalanced by reactivation. ZM 336372-induced activation of c-Raf is not prevented by inhibition of the MAPK cascade, protein kinase C or phosphatidylinositide 3-kinase[1]. ZM 336372 (1 μM) abolishes the upregulation of eNOS after treatment with hydrogen peroxide [2]. ZM 336372 treatment in carcinoid tumor cells results in progressive phosphorylation of Raf-1, mitogen-activated protein kinase 1/2, and extracellular signal-regulated kinase 1/2, and causes a significant reduction of bioactive hormone levels as well as the transcription factor, human achaete-scute homologue-1. Furthermore, ZM 336372 treatment leads to a marked suppression of cellular proliferation and induction of the cell cycle inhibitors p21 and p18 [3].

PF-4708671 is a novel cell-permeable inhibitor of S6K1 (p70 ribosomal S6 kinase 1), with a Ki of 20 nM and IC50 of 160 nM.IC50 Value: 160 nM [1]Target: S6K1PF-4708671 is a novel cell-permeable inhibitor of S6K1, which specifically inhibits the S6K1 isoform with a Ki of 20 nM and IC50 of 160 nM. PF-4708671 prevents the S6K1-mediated phosphorylation of S6 protein in response to IGF-1 (insulin-like growth factor 1), while having no effect upon the PMA-induced phosphorylation of substrates of the highly related RSK (p90 ribosomal S6 kinase) and MSK (mitogen- and stress-activated kinase) kinases. PF-4708671 was also found to induce phosphorylation of the T-loop and hydrophobic motif of S6K1, an effect that is dependent upon mTORC1 (mTOR complex 1). PF-4708671 is the first S6K1-specific inhibitor to be reported and will be a useful tool for delineating S6K1-specific roles downstream of mTOR [1].

BI-D1870 is an ATP-competitive inhibitor of S6 ribosome for RSK1/2/3/4 with IC50 of 31 nM/24 nM/18 nM/15 nM, respectively; 10- to 100-fold selectivity for RSK than MST2, GSK-3β, MARK3, CK1 and Aurora B. BI-D1870 also has a Kd value of 3.5 uM for BRD4.IC50 value: 31/24/18/15 nM (for RSK1/RSK2/RSK3/RSK4); 3.5 uM (BRD4) [1] [2]Target: RSKs; BRD4in vitro: BI-D1870 inhibits RSK1, RSK2, RSK3 and RSK4 with an IC50 of 10–30 nM, but does not significantly inhibit ten other AGC kinase members and over 40 other protein kinases tested at 100-fold higher concentrations. BI-D1870 is cell permeant and prevents the RSK-mediated phorbol ester- and EGF -induced phosphorylation of glycogen synthase kinase-3β and LKB1 in human embry-onic kidney 293 cells and Rat-2 cells. BI-D1870 does not affect the agonist-triggered phosphorylation of substrates for six other AGC kinases. Moreover, BI-D1870 does not suppress the phorbol ester- or EGF-induced phosphorylation of CREB [1]. These experiments confirmed strong interaction with BRD4(1) for the PLK inhibitors BI-2536 (Kd = 37 ± 3 nM) and BI-6727 (Kd = 79 ± 3 nM) and the related RSK inhibitor BI-D1870 (Kd = 3.5 ± 0.17 μM). The closely related JAK inhibitors TG-101348 and TG-101209 bound BRD4(1) with nanomolar affinities (Kd values: 164 ± 10 nM and 123 ±18 nM, respectively) [2].

Latrepirdine (dihydrochloride) is a potent activator of AMPK, also an anti-histamine, promote the removal of α-synuclein protein aggregates. target: AMPKIn vitro: Latrepirdine is shown to up-regulate yeast vacuolar (lysosomal) activity and promote transport of the autophagic marker (Atg8) to the vacuole. Latrepirdine treatment attenuat Aβ42-induced toxicity in wild-type cells but not in the Atg8Δ mutant.[1] In line with a stabilizing effect of latrepirdine on plasma membrane potential, pretreatment with latrepirdine reduced spontaneous Ca2+ oscillations as well as glutamate-induced Ca2+ increases in primary neurons, and protected neurons against glutamate toxicity. Latrepirdine also increased mitochondrial uptake of the voltage-sensitive probe TMRM. [2]In vivo: Treatment with latrepirdine increase AMPK activity in primary mouse motor neuroncultures and in SOD1G93A lumbar spinal cords. Mice "preconditioned" with latrepirdine show a delayed symptom onset and a significant increase in life span. (1 μg/kg, intraperitoneal ).[3]

Fruquintinib (HMPL-013) inhibits VEGFR family member (VEGFR1, 2, 3) with IC50s of 33 nM, 35 nM and 0.5 nM, respectively with weak inhibition of RET, FGFR-1 and c-kit kinases. IC50 value: 33/35/ 0.5 nM (VEGFR1/2/3)Target: VEGFRin vitro: Fruquintinib (HMPL-013) is a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy. Fruquintinib inhibits VEGFR2 (KDR) with an IC50 of 25 nM in the Z-lyte assay. Fruquintinib suppresses VEGF/VEGFR signaling and cell proliferation in HUVECs and HLECs. Fruquintinib inhibits tubule sprouting and prevents angiogenesis. [1]in vivo: Fruquintinib potently inhibits VEGF induced KDR phosphorylation in lung tissue of mouse. Fruquintinib inhibits tumor growth in multiple human xenograft models. [1]A66 is a highly specific and selective p110α inhibitor with IC50 of 32 nM.IRAK-1-4 Inhibitor I is a dual inhibitor of IRAK4 and IRAK1 with IC50 of 0.2 μM and 0.3 μM, respectively.

KU-55933 is a potent ATM inhibitor with an IC50 and Ki of 12.9 and 2.2 nM, respectively, and highly selective for ATM as compared to DNA-PK, PI3K/PI4K, ATR and mTOR.Toceranib(SU 11654; PHA 291639) is a kinase inhibitor with both antitumor and antiangiogenic activity through inhibition of KIT, vascular endothelial growth factor receptor 2, and PDGFRβ.IC50 value:Target: Kit; PDGFRβ; VEGFR2CID-2011756 is a cell-active ATP competitive and specific PKD1 inhibitor that inhibits phorbol ester-induced endogenous PKD1 activation in LNCaP prostate cancer cells.IC50 Value: 10±0.7 uM (cellular inhibition of phospho-Ser916-PKD1 activity) [1]Target: PKDCID 2011756, has pan-PKD inhibitory effects (PKD2 IC50 = 0.6±0.1 uM; PKD3 IC50 = 0.7±0.2 uM) with similar, albeit not identical, potencies which may be expected for an ATP competitive inhibitor. CID 2011756 was the most potent of the inhibitors with a cellular EC50 of 10±0.7 uM (n = 3), an EC50 value comparable to that of our previously described benzoxoloazepinolone.

BLZ945 is a brain-penetrant CSF-1R inhibitor. The biochemical IC50 for CSF-1R is 1 nM, which is >3200-fold higher than its affinity for other kinases. HLM006474 is a potent inhibitor of melanocytes proliferation and subsequent invasion in a three-dimensional tissue culture model system; interferes with E2F activity.IC50 value: 29.8 μM(EC50 in vivo)Target: E2F inhibitorin vivo: HLM006474 is not specific to E2F4 and appears to inhibit binding by all E2F complexes. At 10 and 20-μM concentrations HLM006474 has little effect on E2F4 DNA-binding activity in A375 cells; however at 40-μM E2F4 inhibition is clearly apparent and increases at 60- and 80-μM concentrations.in vivo: The apparent IC50 (drug concentration required to reduce total E2F4 DNA-binding activity by 50% of untreated cells was calculated using the Statistical Analysis System (Proc Probit). Data indicate an in vivo IC50 of 29.8 μM (± 7.6 μM).

TAK-715 is a p38 MAPK inhibitor for p38α with IC50 of 7.1 nM, 28-fold more selective for p38α over p38β, no inhibition to p38γ/δ, JNK1, ERK1, IKKβ, MEKK1 or TAK1.IC50 value: 7.1 nM [1]Target: p38α MAPKin vitro: TAK 715 inhibits LPS-stimulated release of TNF-alpha from THP-1 with IC50 of 48 nM [1]. TAK 715 (10 μM) inhibits Wnt-3a-induced hDvl2 phosphorylation and the hDvl2 shift in U2OS-EFC cells [2]. The amide NH of TAK 715 is hydrogen bonded to the main-chain carbonyl of Met109 of p38 alpha. TAK 715 binds relatively high in the ATP pocket, occupying the hydrophobic back pocket, the adenine region and the front pocket of p38 as well as extending to most of the length of the Gly-rich loop [3].in vivo: TAK 715 (10 mg/kg, po) inhibits LPS-induced TNF-alpha production in mice with 87.6% inhibition. TAK 715 has a modest mouse bioavailability of 18.4% and a slightly improved rat bioavailability of 21.1%. TAK 715 has a modest mouse bioavailability of 18.4% and a slightly improved rat bioavailability of 21.1%. TAK 715 results in Cmax of 0.19 μg/mL and AUC(0-24 hours) of 1.16 μg·h/mL in rats. TAK 715 (30 mg/kg, po) significantly reduces the secondary paw volume with 25 % inhibition in a rat adjuvant-induced arthritis (AA) model [1].

Flavopiridol is a broad inhibitor of CDK, competing with ATP to inhibit CDKs including CDK1, CDK2, CDK4 and CDK6 with IC50 of around 40 nM.Dehydrocorydaline chloride is an alkaloidal that has anti-inflammatory and anti-cancer activities.

SGI-1776 is an inhibitor of Pim kinases, with IC50 of 7 nM, 363 nM, and 69 nM for Pim-1, -2 and -3, respectively.

LY3023414 is a novel, highly soluble, small-molecule, dual kinase inhibitor of class I PI3K isoforms, mTOR, and DNA-PK.ANA-12 is a potent and selective TrkB antagonist, and binds to TrkBECD-Fc with Kd of 12 μM.

NVP-BKM120 is a pan-class I PI3K inhibitor, with IC50 of 52 nM/166 nM/116 nM/262 nM for p110α/β/δ/γ, respectively.

PQR309 is a PI3K inhibitor, inhibits pPKB and pS6 with "++++/+++(+)" in A2058 melanoma cell.

AZ20 is a potent and selective inhibitor of ATR with an IC50 of 5 nM, and has 8-fold selectivity against mTOR (IC50=38 nM).AZD6738 is a potent inhibitor of ATR kinase with an IC50 of 1 nM.

SB 203580 hydrochloride is a p38 MAPK inhibitor with IC50 of 0.3-0.5 μM, also blocks PKB phosphorylation with IC50 of 3-5 μM. AXL1717 is a selective insulin-like growth factor-1 receptor (IGF-1R) inhibitor with IC50 of 1 nM.LTURM34 is a specific DNA-PK inhibitor with an IC50 of 0.034 μM.

GSK2256098 is a selective FAK kinase inhibitor, which inhibits growth and survival of pancreatic ductal adenocarcinoma cells.

OSI-420 is an active metabolite of erlotinib, which is a potent EGFR tyrosin kinase inhibitor.

Duvelisib R enantiomer is the R-enantiomer of Duvelisib. Duvelisib is a novel and selective PI3K δ/γ inhibitor with Ki and IC50 of 23 pM/243 pM and 1 nM/50 nM.Duvelisib is a novel and selective PI3K δ/γ inhibitor with Ki and IC50 of 23 pM/243 pM and 1 nM/50 nM, highly selective for PI3K δ/γ than other protein kinases.

CP-673451 is a potent selective inhibitor of platelet-derived growth factor receptor (PDGFR), and inhibits PDGFR-α and PDGFR-β kinase with IC50s of 10 and 1 nM, respectively.Pexidartinib is a receptor tyrosine kinase (RTK) inhibitor of KIT, CSF1R and FLT3, with potential antineoplastic activity, with IC50 of 28 and 16 nM for Fms and Kit, respectively.

CVT-313 is a potent, selective, reversible, and ATP-competitive inhibitor of CDK2 wirh IC50 of 0.5 μM.

ACHP Hydrochloride is a potent and selective IKK-2 inhibitor with IC50 of 8.5 nM.IC50 value: 8.5 nM [1]Target: IKK-2ACHP Hydrochloride exhibited excellent in vitro profiles (IKK-beta IC(50)=8.5 nM, Cell IC(50)=60 nM) and a strong oral efficacy in in vivo anti-inflammatory assays (significant effects at 1mg/kg, po in arachidonic acid-induced ear edema model in mice).

Acalisib (GS-9820) is a potent and selective inhibitor of PI3Kδ with IC50 value of 12.7 nM. IC50 value: 12.7 nM [1]Target: PI3Kδin vitro: GS-9820 is more selective for PI3Kδ relative to other PI3K class I enzymes (IC50: PI3Kα, 5,441 nM; PI3Kβ, 3,377 nM; PI3Kγ, 1,389 nM; and PI3Kδ, 12.7 nM) . GS-9820 suppresses Fc RI PI3Kδ-mediated CD63 expression with an EC50 of 14 nM, and fMLP PI3Kγ-mediated CD63 expression with an EC50 of 2,065 nM. GS-9820 shows selectivity for PI3Kδ over the other class I PI3K isoforms and virtually no binding to a panel of other kinases. [1]

VX-702 is a highly selective inhibitor of p38α MAPK(IC50=4 -20 nM), 14-fold higher potency against the p38α versus p38β.IC50 value: 4-20 nM [1]Target: p38α MAPKin vitro: Pre-incubation of platelets with VX-702 (1 μM) completely or partially inhibits p38 activation (IC50 4 to 20 nM) induced by platelet agonists including thrombin, SFLLRN, AYPGKF, U46619 and collagen. VX-702 shows no effect on platelet aggregation induced by any of the p38 MAPK agonists in the presence or absence of anti-platelet therapies [1]. VX-702 inhibits the production of IL-6, IL-1β and TNFα (IC50 = 59, 122 and 99 ng/mL, respectively) in a dose-dependent manner [2]. in vivo: The half-life of VX-702 is 16 to 20 hours, with a median clearance of 3.75 L/h and a volume of distribution of 73 L/kg. Both AUC and Cmax values are dose proportional for VX-702, which is predominantly cleared renally [2]. VX-702 (at a dose of 0.1 mg/kg twice daily) has an equivalent effect as that of methotrexate (0.1 mg/kg). In addition, VX-702 (5 mg/kg twice daily) also has an equivalent effect as prednisolone (10 mg/kg once daily), as measured by percentage inhibition of wrist joint erosion and inflammation score [3].PF-06463922 is a potent, dual ALK/ROS1 inhibitor, with Ki of < 0.02 nM, < 0.07 nM, and 0.7 nM for ROS1, ALK (WT), and ALK (L1196M), respectively.

SR-3677 is a potent and selective ROCK-II inhibitor with an IC50 of ~3 nM.AZD6482 is a PI3Kβ inhibitor with IC50 of 10 nM, 8-, 87- and 109-fold more selective to PI3Kβ than PI3Kδ, PI3Kα and PI3Kγ.IC50 value: 10 nMTarget: PI3KβAZD6482 is a PI3Kβ inhibitor (IC50=0.021μM) used in antithrombotic therapy. AZD6482 targets a process that is critical to pathological thrombus formation without interfering with normal haemostasis, which avoids the drawbacks of the existing anti-thrombotic therapy. AZD6482 inhibits PI3Kβ/α/γ/δwith IC50 of 0.021, 1.4, 1.2, 0.08μM, respectively. It washed platelet aggregation with concentration at 6 nM.

PHT-427 is a dual Akt and PDPK1 inhibitor (high affinity binding for the PH domains of Akt and PDPK1) with Ki of 2.7 μM and 5.2 μM, respectively.IC50 value: 2.7/5.2 uM (Ki, Akt/PDPK1) [1]Target: Akt/PDPK1in vitro: PH-427 is a pleckstrin homology domain inhibitor to Akt/PDPK1. PH-427 significantly reduces phospho-Ser241-PDPK1 phospho-Thr308-Akt in PC-3 prostate cancer cells at 10 μM, which shows that PHT-427 could inhibit both Akt and PDKP1. PHT-427 also inhibits translocation of the Akt and PDKP1 PH domains in plasma membrane [1]. PHT-427 induces apoptosis and inhibits AKT phosphorylation with IC50 of 8.6 μM (in BxPC-3 cells), which mainly on its Ser473 residue and less strongly on Thr308 residue without affecting total Akt protein expression. PHT-427 also shows antiproliferation in Panc-1 cells with IC50 of 65 μM [2].in vivo: PHT-427 shows great antitumor activity in BxPC-3 pancreatic, MCF-7 breast and A-549 NSCL cancer xenografts. PHT-427 gives up to an 80% inhibition of tumor growth in BxPC-3 at doses of 125 to 250 mg/kg [1].

Telatinib(Bay 57-9352) is a potent inhibitor of VEGFR2/3, c-Kit and PDGFRα with IC50 of 6 nM/4 nM, 1 nM and 15 nM, respectively.IC50 value:Target: multikinase inhibitorin vitro: Telatinib displays little inhibitory activity against the Raf kinase pathway, epidermal growth factor receptor family, the fibroblast growth factor receptor (FGFR) family, and the Tie-2 receptor [2]. Telatinib has 0.66, 0.17, and 2.5 times higher IC50 values for VEGFR3, c-Kit, and PDGFRβ than VEGFR2, respectively, while Vatalanib exhibits 18, 20, and 16 times higher IC50 values, respectively, indicating that Telatinib has potential benefit over Vatalanib. Telatinib inhibits VEGFR2 autophosphorylation in a whole-cell assay with an IC50 of 19 nM, suppresses VEGF-dependent proliferation of human umbilical vein endothelial cells with an IC50 of 26 nM, and blocks PDGF-stimulated growth of human aortic smooth muscle cells with an IC50 of 249 nM [3].in vivo: Administration of Telatinib as a single agent exhibits a potent anti-tumor activity in multiple human tumor xenograft models including MDA-MB-231 breast cancer, Colo-205 colon cancer, DLD-1 colon cancer, and H460 non-small cell lung cancer, as well as pancreatic and prostate carcinoma in a dose-dependent manner [4].

PF-670462 is a potent (IC50 = 7.7 ± 2.2 nM) and selective (>30-fold with respect to 42 additional kinases) inhibitor of CK1ε in isolated enzyme preparations.IC50 value: 7.7 nM Target: CK1εPF-670462, a selective CK1 ε/δ inhibitor, causes a significant phase delay in animal models of circadian rhythm; it remains unclear whether one of the kinases has a predominant role in regulating the circadian clock. In transfected whole cell assays, it caused a concentration-related redistribution of nuclear versus cytosolic PER. When tested in free-running animals, 50 mg/kg s.c. PF-670462 produced robust phase delays when dosed at circadian time (CT)9 (-1.97 ± 0.17 h). PF-670462 attenuates methamphetamine-stimulated locomotion in vivo.

AT7867 Hcl is a potent ATP-competitive inhibitor of Akt1/2/3 and p70S6K/PKA with IC50 of 32 nM/17 nM/47 nM and 85 nM/20 nM, respectively; little activity outside the AGC kinase family.IC50 value: 32 nM/17 nM/47 nM(Akt1/2/3) [1]Target: Aktin vitro: AT7867 also inhibits structurally related AGC kinases p70S6K and PKA with IC50 of 20 nM and 85 nM, respectively. AT7867 shows ATP-competitive activity to Akt2 with Ki of 18 nM. AT7867 exhibits antiproliferation in cell lines with PTEN or PIK3CA mutations and shows great potent to MES-SA, MDA-MB-468, MCF-7, HCT116 and HT29 with IC50 of 0.94 μM, 2.26 μM, 1.86 μM, 1.76 μM and 3.04 μM, respectively. AT7867 also suppresses the cell growth of U87MG, PC-3 and DU145 cells with IC50 of 8.22 μM, 10.37 μM and 11.86 μM, respectively. AT7867 suppresses Akt activity by inhibiting phosphorylation of GSK-3β in human tumor cells with IC50 of 2-4 μM. AT7867 also induces the phosphorylation of the following Akt direct substrates including proapoptotic transcription factors FKHR (FoxO1a), FKHRL1 (FoxO3a) and the downstream target S6RP in U87MG cells.in vivo: AT7867 shows bioavailability of 44% in mice by p.o. route. AT7867 could increase the cleaved PARP in MES-SA xenografts at 20 mg/kg i.p. or 90 mg/kg p.o.. AT7867 significantly inhibits the tumor growth in MES-SA xenografts or U87MG xenografts with T/C of 0.37 and 0.51, respectively.GS-9973 is an orally bioavailable, selective Syk inhibitor with IC50 of 7.7 nM.

ZZZM 323881 Hcl is a potent and selective VEGFR2 inhibitor with IC50 of <2 nM, almost no activity on VEGFR1, PDGFRβ, FGFR1, EGFR and ErbB2.IC50 value: <2 nM [1]Target: VEGFR2ZM323881 inhibits VEGF-A, EGF and bFEF induced HUVEC cell proliferation with IC50 of 8 nM, 1.9 μM and 1.6 μM, respectively. ZM323881 (10 nM) abolishes VEGF-A-mediated increases in vascular permeability in perfused mesenteric microvessels in male leopard. ZM323881 (10 nM) blocks the increase in intensity of the VEGF-R2 band in the lung of male leopard frogs [1]. M323881 (1 μM) blocks activation of extracellular regulated-kinase, p38, Akt, and endothelial nitric oxide synthetase (eNOS) by VEGF, but did not inhibit p38 activation by the VEGFR-1-specific ligand, placental growth factor (PIGF) in human aortic endothelial cells (HAECs). ZM323881 (1 μM) also perturbes VEGF-induced membrane extension, cell migration, and tube formation by HAECs. ZM323881 (1 μM) reverses VEGF-stimulated phosphorylation of CrkII and its Src homology 2 (SH2)-binding protein p130Cas, which are known to play a pivotal role in regulating endothelial cell migration [2]. ZM323881 (10 nM) completely blocks VEGF-induced VEGF promoter activity in SCC-9 cells. ZM323881 (10 nM) blocks VEGF stimulated Hif-1α protein accumulation in SCC-9 cells [3]. ZM323881 (10 nM) blocks VEGF-induced Rac1 activation at 30 min in HUVECs. ZM323881 (10 nM) prevents Vav2 tyrosine phosphorylation in response to VEGF in HUVECs [4].

NT157is a selective inhibitor of IRS-1/2, IC50 values at sub-micromolar doses (ranging from 0.3 to 0.8 μM) .IC50 value: 0.3 to 0.8 μM [1]Target: Insulin receptorin vitro: NT157 significantly affects the cells' migratory ability, as confirmed by a wound-healing assay. NT157 induces cytostatic effects, as evidenced by G2/M cell cycle arrest, and does not affect apoptosis. NT157, a novel small-molecule that specifically targets IRS protein, in OS cells. NT157 is a small-molecule inhibitor that induces Ser-phosphorylation and consequently the degradation of IRS-1 and IRS-2. NT157 efficiently affects migration ability of MG-63 and U-2OS OS cells. NT157 treatment induces cell cycle arrest and inhibits IGF system signaling. [1] The density of LNCaP cells grown in FBS was decreased approximately 20% at 1 μM, approximately 70% at 2 μM, and >90% at 5 μM (IC50, 1.4 μM). Growth of LNCaP cells is suppressed >60% when cultured in CSS but still exhibited significant density at 2 μM and maximal decreased density at 5 μM. The density of FBS-cultured PC3 cells was similarly decreased by NT157 treatment (40% at 2 μM and > 70% at 5 μM; IC50, 2.5 μM). [2]in vivo: NT157 suppresses growth of LNCaP xenografts following castration. NT157 treatment affects IGF1R and IRS targets in xenografts and significantly delays castration-resistant progression of LNCaP androgen-responsive xenografts when combined with castration. NT157 potentiates docetaxel activity in PC3 xenografts.[2]

INCB28060 is a potent and selective c-MET kinase inhibitor. INCB28060 inhibits c-MET kinase activity with an average IC50 of 0.13 nM. BIX02188 is a selective inhibitor of MEK5 with IC50 of 4.3 nM, also inhibits ERK5 catalytic activity with IC50 of 810 nM, and does not inhibit closely related kinases MEK1, MEK2, ERK2, and JNK2.IC50 value: 4.3 nMTarget: MEK5in vitro: BIX02188 significantly blocks MEK5 catalytic activity with IC50 of 4.3 nM and inhibits ERK5 catalytic activity with IC50 of 0.83 μM. It shows no activity against closely related kinases MEK1, MEK2, ERK1, p38α, JNK2, TGFβR1, EGFR, and STK16 with IC50 values of 1.8 μM for TGFβR1, 3.9 μM for p38α, and >6.3 μM for other kinases. Pretreatment with BIX02188 inhibits sorbitol-induced phosphorylation of ERK5 in HeLa cells in a dose dependent manner and displays no inhibitory activity against the phosphorylation of ERK1/2, p38, and JNK1/2 MAPKs. BIX02188 treatment alone for 24 hours in HeLa or HEK293 cells does not show any cytotoxic effect. BIX02188 inhibits transcriptional activation of MEF2C through the MEK5/ERK5 signaling cascade in active MEK5/ERK5/MEF2C-driven luciferase expression system in HeLa and HEK293 cells with IC50 values of 1.15 μM and 0.82 μM, respectively [1]. BIX02188 also inhibits phosphorylation of BMK1 in bovine lung microvascular endothelial cells (BLMECs) which are stimulated with 300 μM H2O2, in a dose-dependent manner, with IC50 of 0.8 μM, specifically by blocking the MEK5 signal pathway. BIX02188 completely reverses the inhibitory effect on TNF-mediation; JNK activation had a similar effect on BMK1 inhibition, suggesting that it inhibits TNF signaling through activation of the MEK5-BMK1 signaling pathway [2].KU-57788 is a potent and selective inhibitor of DNA-PK, a modest inhibitor of BRD4 and BRDT, with IC50s of 13 nM, 1 μM and 3.5 μM, respectively, and also increases CRISPR/Cas9-mediated editing frequencies.PLX-4720 is a potent and selective inhibitor of B-RafV600E with IC50 of 13 nM in a cell-free assay, equally potent to c-Raf-1(Y340D and Y341D mutations), and 10-fold selectivity for B-RafV600E than wild-type B-Raf.

GNE-317 is a potent PI3K/mTOR inhibitor that can cross the blood–brain barrier; shows potent suppression of the PI3K pathway in the brain of mice with intact BBB.IC50 value:Target: PI3K/mTOR inhibitorin vitro: GNE-317 was not impacted by the overexpression of the human or mouse P-gp and BCRP, and suggesting that this compound was a poor substrate of these transporters. GNE-317 markedly inhibited the PI3K pathway in mouse brain, causing 40% to 90% suppression of the pAkt and pS6 signals up to 6-hour postdose [1]. in vivo: GNE-317 was efficacious in the U87, GS2, and GBM10 orthotopic models, achieving tumor growth inhibition of 90% and 50%, and survival benefit, respectively [1]. GNE-317 was uniformly distributed throughout the brain in the U87 and GS2 models [2].

SKLB610, a novel multi-targeted inhibitor, inhibits angiogenesis-related tyrosine kinase VEGFR2, FGFR2 and PDGFR at rate of 97%, 65% and 55%, respectively, at concentration of 10 μM in biochemical kinase assays.IC50 Value: Target: VEGFR; FGFR2; PDGFRin vitro: SKLB610 inhibited angiogenesis-related tyrosine kinase VEGFR2, fibroblast growth factor receptor 2 (FGFR2) and platelet-derived growth factor receptor (PDGFR) at rate of 97%, 65% and 55%, respectively, at concentration of 10μM in biochemical kinase assays. In vitro, SKLB610 showed more selective inhibition of VEGF-stimulated human umbilical vein endothelial cells (HUVECs) proliferation, and this proliferation inhibitory effect was associated with decreased phosphorylation of VEGFR2 and p42/44 mitogen-activated protein kinase (p42/44 MAPK). Antiangiogenic evaluation showed that SKLB610 inhibited the HUVECs capillary-tube formation on Matrigel in vitro and the sub-intestinal vein formation of zebrafish in vivo. Moreover, SKLB610 inhibited a panel of human cancer cells proliferation in a concentration-dependent manner and human non-small cell lung cancer cell line A549 and human colorectal cancer cell line HCT116 were most sensitive to SKLB610 treatment [1].in vivo: Chronic intraperitoneally administration of SKLB610 at dose of 50mg/kg/d resulted in significant inhibition in the growth of established human A549 and HCT116 tumor xenografts in nude mice without exhibit toxicity. Histological analysis showed significant reductions in intratumoral microvessel density (CD31 staining) of 43-55% relative to controls depending on the specific tumor xenografts. In conclusion, the present study demonstrated that SKLB610 exhibited its antitumor activity as a multi-targeted inhibitor with more potent inhibition of VEGFR2 activity [1]. Pharmacokinetic studies in rats demonstrated that the oral bioavailability of SKLB610 in nanosuspension (89.4%) was 2.6-fold higher than in coarse suspension (34.1%). Stabilizer type, milling time, and milling speed had a significant effect on particle size of the SKLB610 nanosuspensions [2].

CAL-101 is a highly selective and potent p110δ inhibitor with IC50 of 2.5 nM, is 40- to 300-fold more selective for p110δ relative to other PI3K class I enzymes (p110α, p110β, and p110γ; IC50 are 820, 565, and 89nM, respectively).

Tomatidine inhibits the phosphorylation of ERK, Akt, and the nuclear content of NF-κB. possess anti-inflammatory properties. a novel small molecule inhibitor of muscle atrophy. target: ERK[1], Akt[1], NF-κB[1];In vitro: Tomatidine downregulates the expression of MMP-2, -9, while increases the expression of RECK and TIMP-1. Tomatidine does not effectively inhibit the viability of A549 cells. tomatidine inhibits the invasion of A549 cells by reducing the expression of MMPs. [1] tomatidine stimulated mTORC1 signaling and anabolism, leading to accumulation of protein and mitochondria, and ultimately, cell growth. [2] tomatidine inhibits the invasion of A549 cells by reducing the expression of MMPs. [3] In vivo: in mice, tomatidine increased skeletal muscle mTORC1 signaling, reduced skeletal muscle atrophy, enhanced recovery from skeletal muscle atrophy, stimulated skeletal muscle hypertrophy, and increased strength and exercise capacity. [2] GSK2656157 is an ATP-competitive inhibitor of PERK enzyme activity with an IC50 value of 0.9 nM, and highly selective for PERK with IC50 values of > 100 nM against a panel of 300 kinases.

KRN-633 is a cell-permeable, reversible, ATP-competitive VEGFR kinase inhibitor with IC50 of 170 nM, 160 nM, and 125 nM for VEGFR-1, VEGFR-2, VEGFR-3, respectively.IC50 value: 170 nM/160 nM/125 nM (VEGFR1/2/3) [1]Target: VEGFRin vitro: KRN 633, a novel quinazoline urea derivative, strongly inhibits VEGFR1, VEGFR2 and VEGFR3 receptors with IC50 values of 170 nM, 160 nM and 125 nM respectively. It shows lower inhibitory activity towards non-RTKs, such as PDGF receptor (PDGFRα and β, c-Kit, breast tumor kinase, and tunica interna endothelial cell kinase tyrosine kinases (IC50 = 965, 9850, 4330, 9200, and 9900 nM, respectively). KRN 633 potently inhibits ligand VEGF induced phosphorylation of VEGFR2 in HUVECs with an IC50 of 1.16 nM. KRN 633 also inhibits VEGF-dependent, but not bFGF-dependent, phosphorylation of the MAP kinases in endothelial cells, with IC50 values of 3.51 nM and 6.08 nM for ERK1 and ERK2, respectively. KRN633 has also been shown to inhibit the VEGF-driven proliferation of HUVECs with an IC50 of 14.9 nM, but it only suppresses FGF-driven proliferation at 3 μM weakly [1]. KRN 633 inhibits hypoxia-induced transcriptional activation of HIF-1α in a concentration-dependent manner with an IC50 of 3.79 μM, through the inhibition of both Akt and ERK phosphorylation signaling pathways [2].in vivo: Although not cytotoxic to various cancer cells in vitro, KRN633 exhibits excellent antitumor activity in vivo due to its inhibitory effect on tumor vessel formation and vascular permeability. Once-daily administration of KRN633 at 100 mg/kg/d produces significant tumor growth inhibition in A549, LC-6-LCK, HT29, Ls174T, LNCap and Du145 cells while twice-daily administration of KRN633 at 100 mg/kg induces ~90% growth inhibition of HT29 tumors [1]. Treatment of mid-pregnancy mice with KRN 633 (300 mg/kg, p.o.) reduces the blood supply to fetal tissues due to diminished vascularization in both placenta and fetal organs and consequently increases the risk of induction of intrauterine growth restriction (IUGR) [3].

ZSTK474 inhibits class I PI3K isoforms with IC50 of 37 nM, mostly PI3Kδ. IC50 value: 37 nM [1]Target: class I PI3Kin vitro: ZSTK474 at 1 μM potently reduces PI3K activity to 4.7% of the control level, whereas LY2194002 only reduces the activity to 44.6% of the control. ZSTK474 inhibits the activities of recombinant p110β, -γ, and -δ with IC50 of 17 nM, 53 nM, and 6 nM, respectively. ZSTK474 shows potent antiproliferative activity against a panel of 39 human cancer cell lines with mean GI50 of 0.32 μM, more effectively than that of LY294002 or wortmannin with mean GI50 of 7.4 μM or 10 μM, respectively. ZSTK474 treatment at 1 μM blocks membrane ruffling and generation of PIP3 induced by platelet-derived growth factor in murine embryonic fibroblasts (MEFs). ZSTK474 at 10 μM induces apoptosis in OVCAR3 cells, and induces complete G1-phase arrest but not apoptosis in A549 cells. ZSTK474 treatment at 0.5 μM significantly decreases the level of phosphorylated Akt and GSK-3β, as well as the cyclin D1 protein expression. ZSTK474 also inhibits the phosphorylation of other downstream signaling components that are involved in regulating cell proliferation including FKHRL1, FKHR, TSC-2, mTOR, and p70S6K in a dose-dependent manner [1]. ZSTK474 does not inhibit mTOR at 0.1 μM, and even at a concentration of 100 μM, ZSTK474 inhibits mTOR activity less than 40% [2]. in vivo: Oral administration of ZSTK474 inhibits the growth of subcutaneously implanted mouse B16F10 melanoma tumors in a dose-dependent manner, producing tumor regression of 28.5%, 7.1%, or 4.9% on day 14 at 100, 200, or 400 mg/kg, respectively, which is superior to that of the four major anticancer drugs irinotecan, cisplatin, doxorubicin, and 5-fluorouracil at their respective maximum tolerable doses with tumor regression of 96%, 35.7%, 24%, or 68.3%, respectively. ZSTK474 treatment at 400 mg/kg completely inhibits the growth of A549, PC-3, and WiDr xenografts in mice, and induces the regression of A549 xenograft tumors [1]. ZSTK474 significantly inhibits tumor growth in the RXF-631L xenograft model, correlated with a significantly reduced number of microvessels in the ZSTK474-treated mice [3].

TP-3654 is a second-generation Pim kinase inhibitor with Ki values of 5 and 42 nM for Pim-1 and Pim-3, respectively.

Vatalanib (PTK787; ZK-222584; CGP-79787) is an inhibitor of VEGFR2/KDR with IC50 of 37 nM.

HS-173 is a novel PI3K inhibitor, that is used for cancer treatment.

AM-2394 is a structurally distinct glucokinase activator (GKA). AM-2394 activates glucokinase (GK) with an EC50 of 60 nM.

CC-401 hydrochloride is a potent inhibitor of all three forms of JNK with Ki of 25 to 50 nM.

Vps34-IN-1 is an inhibitor of Vps34 extracted from patent WO/2012085815 A1, compound example 16a; has an IC50 of 4 nM.

GSK2141795 is a potent and selective pan-Akt inhibitor with IC50 values of 180/328/38 nM for Akt1/Akt2/Akt3, respectively.BMS-3 is a potent inhibitor of LIMK1.LIM kinase 1 (LIMK1) activity is essential for cell migration and cell cycle progression.

Erlotinib hydrochloride inhibits purified EGFR kinase with an IC50 of 2 nM.PRT062607 hydrochloride is a highly specific and potent inhibitor of purified Syk (IC50 1-2 nM).AS703026 is a highly selective, potent, ATP non-competitive allosteric inhibitor of MEK1/2, used for cancer treatment.

GSK429286A is a selective inhibitor of ROCK1 and ROCK2 with IC50 values of 14 nM and 63 nM, respectively.LDC4297 is a potent and selective CDK7 inhibitor with an IC50 of 0.13 nM.

GSK2636771 is a potent, selective and orally bioavailable PI3Kβ inhibitor, sensitive to PTEN null cell lines.CUDC-101 is a potent inhibitor of HDAC, EGFR, and HER2 with IC50s of 4.4, 2.4, and 15.7 nM, respectively.

TBB is a selective inhibitor for the protein kinase CK2 with IC50 of 1.6 μM.VX-745 is a potent and selective inhibitor of p38α, and possesses anti-inflammatory activity.

GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, is a selective non-ATP competitive inhibitor of Bcr-Abl with an IC50 value of 0.22±0.1 uM (Wild type Abl).IC50 Value: 0.22±0.1 uM (Wild type Abl) [1]Target: Abl GNF-5 is a cell-permeable GNF-2 N-hydroxyethyl carboxamide analog that exhibits in vivo efficacy in suppressing the proliferation of Bcr-abl-expressing Ba/F3 (93% and 83% of no-treatment control, respectively, on days 5 and 7 post treatment; 100 mg/kg b.i.d.) and bone marrow cells (~75% of no-treatment control in both WBC counts and spleen weight on day 7 post treatment; 50 mg/kg b.i.d.) in murine xenograft models of leukemia. Similar to GNF-2, GNF-5 exerts its effect via an allosteric mechanism (IC50 = 0.22 M against wild-type Abl) by targeting the myristate-binding pocket near the c-terminus of Abl kinase domain and thereby altering the conformational dynamics of the ATP-binding pocket. GNF-5 is ineffective toward the myristate-binding site mutant E505K and the ATP-binding site 'gatekeeper' mutant T315I.

AT7519 hydrochloride is a multi-CDK inhibitor for CDK1, 2, 4, 6 and 9 with IC50 of 10-210 nM; is less potent to CDK3 and little active to CDK7. IC50 Value: 10-210 nMTarget: CDK1/2/4/6/9in vitro: AT7519 is an ATP competitive CDK inhibitor with a Ki value of 38 nM for CDK1. AT7519 is inactive against all non-CDK kinases with the exception of GSK3β (IC50 = 89 nM). AT7519 shows potent antiproliferative activity in a variety of human tumor cell lines with IC50 values ranging from 40 nM for MCF-7 to 940 nM for SW620 consistent with the inhibition of CDK1 and CDK2. AT7519 induces dose-dependent cytotoxicity in multiple myeloma (MM) cell lines with IC50 values ranging from 0.5 to 2 μM at 48 hours, with the most sensitive cell lines being MM.1S (0.5 μM) and U266 (0.5 μM) and the most resistant MM.1R (>2 μM). It does not induce cytotoxicity in peripheral blood mononuclear cells (PBMNC). AT7519 partially overcomes the proliferative advantage conferred by IL6 and IGF-1 as well as the protective effect of bone marrow stromal cells (BMSCs). AT7519 induces rapid dephosphorylation of RNA pol II CTD at serine 2 and serine 5 sites, and leads to the inhibition of transcription, partially contributing to AT7519 induced cytotoxicity of MM cells. AT7519 induces activation of GSK-3β by down-regulating GSK-3β phosphorylation, which also contributes to AT7519 induced apoptosis independent of the inhibition of transcription.in vivo: A twice daily dosing of AT7519 (9.1 mg/kg) causes tumor regression of both early-stage and advanced-stage s.c. tumors in the HCT116 and HT29 colon cancer xenograft models. AT7519 treatment (15 mg/kg) inhibits tumor growth and prolongs the median overall survival of mice in the human MM xenograft mouse model in association with increased caspase 3 activation.

CHIR-124 is a potent and selective Chk1 inhibitor with IC50 of 0.3 nM, and also potently targets PDGFR and FLT3 with IC50s of 6.6 nM and 5.8 nM.Linsitinib is a selective inhibitor of IGF-1R with IC50 of 35 nM, and modestly potent to InsR with IC50 of 75 nM, and has no activity towards Abl, ALK, BTK, EGFR, FGFR1/2, PKA etc.

URMC-099 is an orally bioavailable, brain penetrant inhibitor of Mixed Lineage Kinase 3(MLK3) with IC50 of 14 nM; inhibits LPS-induced TNFα release in microglial cells, HIV-1 Tat-induced release of cytokines in human monocytes, and up-regulation of phospho-JNK in Tat-injected brains of mice.IC50 value: 14 nM [1]Target: MLK3 inhibitorin vitro: URMC-099 shows excellent brain exposure in mouse PK models and minimal interference with key human CYP450 enzymes or hERG channels. inhibits LPS-induced TNFα release in microglial cells, HIV-1 Tat-induced release of cytokines in human monocytes and up-regulation of phospho-JNK in Tat-injected brains of mice. URMC-099 likely functions in HAND preclinical models by inhibiting multiple kinase pathways, including MLK3 and LRRK2 (IC50 = 11 nM) [1]. URMC-099 treatment reduced inflammatory cytokine production by HIV-1 Tat-exposed microglia and prevented destruction and phagocytosis of cultured neuronal axons by these cells [2].in vivo: URMC-099 treatment reduced inflammatory cytokine production, protected neuronal architecture, and altered the morphologic and ultrastructural response of microglia to HIV-1 Tat exposure [2].AVL-292 is a potent inhibitor of Btk kinase activity (IC50<0.5 nM, Kinact/Ki=7.69×104 M-1s-1s) in biochemical assays.BAW2881 is a potent and selective VEGFR inhibitor (vascular endothelial growth factor receptor tyrosine kinase inhibitor) with activity to inhibit chronic and acute skin inflammation.target: VEGFRIC 50: 37 nmol/LIn vitro: BAW2881 block VEGF-A-induce proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) and lymphatic endothelial cells (LECs)In vivo: In a transgenic mouse model of psoriasis, NVP-BAW2881 reduce the number of blood and lymphatic vessels and infiltrating leukocytes in the skin, and normalize the epidermal architecture. NVP-BAW2881 also display strong anti-inflammatory effects in models of acute inflammation. Pretreatment with topical NVP-BAW2881 significantly inhibited VEGF-A-induced vascular permeability in the skin of pigs and mice.NVP-BAW2881 can dissolve in polyethylene glycol-200 and orally administered to mice in a dose of 25 mg/kg/day in 10 ml/kg.

HMN-214(IVX214) is a potent PLK1 inhibitor an average IC50 of 0.12 μM.IC50 Value: 0.12 μMTarget: PLK1in vitro: HMN-214 is an oral prodrug that is rapidly converted to HMN-176. The in vitro data of HMN-214 are scarce. However, HMN-176, active metabolite of HMN-214, shows potent and broad-spectrumanti-tumor activity against various cancer cells, including HeLa, PC-3, DU-145, MIAPaCa-2, U937, MCF-7, A549, and WiDr, with a mean IC50 value of 118 nM. HMN-176 is also cytotoxic to drug-resistant human and murine cell lines, including P388/CDDP, P388/VCR, K2/CDDP, and K2/VP-16, with IC50 values ranging from 143 nM–265 nM. In HeLa cells, HMN-176 (3 μM) blocks cell cycle at G2/M phase. In Doxorubicin-resistant K2/ARS cells, HMN-176 inhibits cell growth with an IC50 value of 2 μM. HMN-176 (3 μM) down-regulates the expression of the multidrug resistance gene (MDR1), due to the disturbance of NF-Y transcription factor binding to the MDR1 promoter. In human RPE1 and CFPAC-1 cells, HMN-176 (2.5 μM) delays satisfaction of the spindle assembly checkpoint. HMN-176 (250 nM–2.5 μM) inhibits meiotic spindle assembly and aster formationin Spisula oocytes. HMN-176 (2.5 μM) also inhibits aster microtubule formation from human centrosomes. These results indicate that the anti-tumor activity of HMN-176 is at least partially via disrupting centrosome-mediated MT assembly during mitosis. in vivo: HMN-214 is an oral pro-drug of HMN-176 with improved oral absorption. HMN-214 (30 mg/kg) triggers no obvious neurotoxicity in mice. In mouse xenograft model of PC-3, A549, and WiDr cells, HMN-214 (10 mg/kg–20 mg/kg) inhibits tumor growth. In nude mice model bearing multidrug-resistant KB-A.1 cells, HMN-214 (10 mg/kg–20 mg/kg) significantly suppresses MDR1 mRNA expression.

LY3009120 is a pan RAF and RAF dimer inhibitor, and inhibits BRAFV600E, BRAFWT and CRAFWT with IC50 values of 5.8, 9.1 and 15 nM, respectively.PF-04691502 is a potent and selective inhibitor of PI3K and mTOR kinases with antitumor activity. PF-04691502 inhibits human and mouse PI3Kα with Ki of 1.8 and 1.2 nM, respectively, human PI3K isoforms β, δ, and γ with Ki of 2.1, 1.6, and 1.9 nM, respectively, and human mTOR with Ki of 16 nM.

GSK-690693 is a pan-Akt inhibitor targeting Akt1/2/3 with IC50 of 2/13/9 nM in cell-free assays, also sensitive to the AGC kinase family: PKA, PrkX and PKC isozymes.

U0126 is a non-ATP competitive MEK inhibitor, with IC50 of 70 nM and 60 nM for MEK1 and MEK2, respectively.

Lenvatinib is an orally active, multi-target inhibitor, mostly for VEGFR2(KDR)/VEGFR3(Flt-4) with IC50 of 4 nM/5.2 nM, and less potent against VEGFR1/Flt-1, and appr 10-fold more selective for VEGFR2/3 against FGFR1, PDGFRα/β.Afuresertib is an orally available, ATP-competitive, pan-AKT inhibitor with Ki of 0.08, 2 and 2.6 nM against AKT1, AKT2 and AKT3, respectively.

Icotinib Hcl(BPI-2009H) is a potent and specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with an IC(50) of 5 nM, including it's mutants of EGFR(L858R), EGFR(L861Q), EGFR(T790M) and EGFR(T790M, L858R).IC50 value: 5 nMTarget: EGFR and EGFR mutantsin vitro: Icotinib inhibits EGFR activity in a dose-dependent manner, with an IC50 value of 5 nM and complete inhibition at 62.5 nM. Icotinib selectively solely inhibits the EGFR members including the wild type and mutants with inhibition efficacies of 61-99%. Icotinib blocks EGFR-mediated intracellular tyrosine phosphorylation in human epidermoid carcinoma A431 cells in a dose-dependent manner. Meanwhile, in our proliferation assay performed on A431, BGC-823, A549, H460, HCT8, KB and Bel-7402 cell lines, we found that the relative sensitivity of cell lines to Icotinib is A431 > BGC-823 > A549 > H460 > KB > HCT8 and Bel-7402. Icotinib exhibits a broad spectrum of antitumor activity and it is especially effective against tumors expressing higher levels of EGFR [1].in vivo: In vivo studies demonstrated that Icotinib exhibited potent dose-dependent antitumor effects in nude mice carrying a variety of human tumor-derived xenografts. The drug was well tolerated at doses up to 120 mg/kg/day in mice without mortality or significant body weight loss during the treatment. A head to head randomized, double blind phase III trial using Gefitinib as an active control for patients with advanced non-small cell lung cancer (NSCLC) was finished recently (Trial registration ID: NCT01040780) [1].

LOXO-101 is a potent, ATP competitive TRK inhibitor with IC50s in low nanomolar range for inhibition of all TRK family members in binding and cellular assays, with 100x selectivity over other kinases, with 2 to 20 nM cellular potency against the TRKA, TRKB, and TRKC kinases.In vivo: A single dose (30 mg/kg) of LOXO-101 reduced tyrosine phosphorylation of TRKA and downstream signal transduction (pERK) in the tumor >80%. LOXO-101 was well tolerated up to 200 mg/kg/day for 14 d in this model.In vitro: LOXO-101 was evaluated for off-target kinase enzyme inhibition against a panel of 226 non-TRK kinases at a compound concentration of 1,000 nM and ATP concentrations near the Km for each enzyme. LOXO-101 demonstrated greater than 50% inhibition for only one non-TRK kinase (TNK2 IC50 = 576 nM).

Nandrolone decanoate is an anabolic steroid used in doping.IC50 value:Target:in vivo: Nandrolone decanoate has beneficial effects on weight, lean body mass and quality of life in selected patients who have mild to moderate HIV wasting.AZD5363 is a potent pan-AKT kinase inhibitor with IC50 of 3, 7 and 7 nM for Akt1,2 and 3, respectively.

ON123300 is a potent inhibitor of CDK4, with an IC50 of 3.8 nM, with little inhibitory activity against CDKs 1,2,5 and 8.IC50 value: 3.8 nM [1]Target: CDK4in vitro: ON123300 is a novel kinase inhibitor, inhibits CDK4/6 and PI3K-δ and exhibits potent activity against mantle cell lymphomas (MCLs). [1] ON123300 is a low molecular weight multi-kinase inhibitor identified through a series of screens that supported further analyses for brain tumor chemotherapy. Biochemical assays indicated ON123300 was a strong inhibitor of Ark5 and CDK4 as well as growth factor receptor tyrosine kinases such as Beta-type platelet-derived growth factor receptor [PDGFRβ]. ON123300 inhibited U87 glioma cell proliferation with an IC50 = 3.4 ± 0.1 μM and reduced phosphorylation of Akt, yet it also unexpectedly induced Erk activation; both in a dose- and time-dependent manner that subsequently was attributed to relieving Akt-mediated C-Raf S259 inactivation and activating a p70S6K initiated PI3K negative feedback loop. [3]

AZ191 is a potent small molecule inhibitor that selectively inhibits DYRK1B with IC50 of 17 nM; selective for DYRK1B over both DYRK1A and DYRK2.IC50 value: 17 nM [1]Target: DYRK1B inhibitorin vitro: Using in vitro kinase assays, phospho-specific immunoblot analysis and MS in conjunction with AZ191 we now show that DYRK1B phosphorylates CCND1 at Thr(286), not Thr(288), in vitro and in cells. In HEK (human embryonic kidney)-293 and PANC-1 cells (which exhibit DYRK1B amplification) DYRK1B drives Thr(286) phosphorylation and proteasome-dependent turnover of CCND1 and this is abolished by AZ191 or DYRK1B RNAi, but not by GSK3β inhibitors or GSK3β RNAi.

BMS-5 is a Potent LIM kinase inhibitor (IC50 values are 7 and 8 nM for LIMK1 and LIMK2 respectively).Inhibits cofilin phosphorylation in MDA-MB-231 breast cancer cells. Reduces MDA-MB-231 tumor cell invasion in a 3D matrigel invasion assay.

MK-8745 is a potent and selective Aurora A inhibitor with IC50 of 0.6 nM, more than 450-fold selectivity for Aurora A over Aurora B.target: Aurora A, Aurora BIC50: 0.6 nM [1]MK-8745, a novel Aurora-A specifi c inhibitor, leads to cell cycle arrest at the G2/M phase with accumulation of tetraploid nuclei followed by cell death in non-Hodgkin lymphoma (NHL) cell lines[2]. MK8745 induced apoptotic cell death in a p53-dependent manner. Exposure of p53 wild-type cells to MK8745 resulted in the induction of p53 phosphorylation (ser15) and an increase in p53 protein expression.[1] MK-8745 can aff ect downstream targets of Aurora-A and induce apoptotic cell death.[2]Purvalanol B(NG-95) is a cyclin-dependent kinase inhibitor with IC50 values of 6, 6, 9, > 10,000, and 6 nM for cdc2/cyclin B, cdk2/cyclin A, cdk2/cyclin E, cdk4/cyclin D1 and cdk5-p35 respectively. IC50 Value: 6 nM(cdc2/cyclin B); 6 nM(cdk2/cyclin A); 9 nM(cdk2/cyclin E); 6 nM(cdk5-p35)[1]Target: cdc2/cyclin B; cdk2/cyclin E; cdk5-p35in vitro: In vitro inhibitory activity against Cyclin-dependent kinase 1-cyclin B complex from starfish oocytes is 6 nM (IC50) [1]. In addition to CDK1, p42/p44 MAPK were found to be two major purvalanol-interacting proteins in five different mammalian cell lines (CCL39, PC12, HBL100, MCF-7 and Jurkat cells), suggesting the generality of the purvalanol/p42/p44 MAPK interaction. When cells were treated with purvalanol, p42/p44 MAPK and CDK1 activities were inhibited in a dose-dependent manner. Furthermore, purvalanol inhibited the nuclear accumulation of p42/p44 MAPK, an event dependent on the catalytic activity of these kinases [2].in vivo:

VRT752271 is a pyrrole inhibitors of ERK protein kinase.IC50 value: Target: ERK

LEE011 is a highly specific CDK4/6 inhibitor with IC50 values of 10 nM and 39 nM, respectively, and is over 1,000-fold less potent against the cyclin B/CDK1 complex.

LY2603618 is a potent and selective inhibitor of Chk1 protein kinase activity in vitro with IC50 of 7 nM.

Sotrastaurin is a potent pan-PKC inhibitor, with Kis of 0.22 nM, 0.64nM, 0.95 nM, 1.8 nM, 2.1 nM and 3.2 nM for PKCθ, PKCβ, PKCα, PKCη, PKCδ and PKCε, respectively.S49076 is a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3 with IC50 values below 20 nM.PCI-32765 is a selective, irreversible Btk inhibitor with IC50 value of 0.5 nM.BIX02189 is a selective MEK5/ERK5 inhibitor with an IC50 of 59 nM.AEE788 is an inhibitor of the EGFR and ErbB2 with IC50 values of 2 and 6 nM, respectively.MEK162 is a potent and selective mitogen-activated protein kinase (MEK) inhibitor wirh IC50 of 12 nM.

BYL-719 is a potent and selective PI3Kα inhibitor with IC50 of 5 nM.

Go 6983 is a pan-PKC inhibitor against for PKCα, PKCβ, PKCγ, PKCδ and PKCζ with IC50 of 7 nM, 7 nM, 6 nM, 10 nM and 60 nM, respectively.

Erdafitinib (JNJ-42756493) is a potent and orally available FGFR family inhibitor; inhibits FGFR1-4 with IC50 values of 1.2, 2.5, 3.0 and 5.7nM, respectively.

Gefitinib is an inhibitor that specifically binds and inhibits the EGFR tyrosine kinase, with the IC50 value of 2-37 nM in NR6wtEGFR cells.

Crizotinib is a potent inhibitor of c-Met and ALK with IC50 of 11 nM and 24 nM in cell-based assays, respectively.

ISRIB (trans-isomer) is a potent inhibitor of PERK with an IC50 of 5 nM.GSK2606414 is an orally available and selective PERK inhibitor with an IC50 of 0.4 nM.

SUN11602 is a novel aniline compound with basic fibroblast growth factor-like activity.SLx-2119 is a selective inhibitor of ROCK2 with IC50 of 105 nM, more than 200 fold selecivity over ROCK1 (IC50=24 μM).

BRAF inhibitor is a potent BRAF inhibitor.

Pazopanib is a novel multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFRβ, c-Kit, FGFR1, and c-Fms with IC50 of 10, 30, 47, 84, 74, 140 and 146 nM, respectively.

XL228 is a protein kinase inhibitor targeting IGF1R, the Aurora kinases, FGFR1-3, ABL and SRC family kinases.IC50 Value: 3 nM (Aurora A Kinase); 5 nM (Ki, Abl)[1]Target: IGF1R; Aurora A; multikinasein vitro: Approximately 30% of the lines demonstrated XL228 IC50 values of <100nM in viability assays, including many lines with characterized ALK or FGFR mutations or amplifications. Cell lines showing the highest level of response to XL228 were often sensitive to other Aurora, ALK or FGFR inhibitors as well. Sub-20nM activity was demonstrated against FGFR2 in a cellular kinase ELISA assay, and confirmed by immunoblot analysis. Potency against ALK in the cell kinase assay was lower (approximately200 nM) [2].in vivo: Clinical trial: Study of XL-228 in Subjects With Chronic Myeloid Leukemia or Philadelphia-Chromosome-Positive Acute Lymphocytic Leukemia. Phase 1

Flavopiridol hydrochloride competes with ATP to inhibit CDKs including CDK1, CDK2, CDK4 and CDK6 with IC50 of ~ 40 nM. It is 7.5-fold more selective for CDK1/2/4/6 than CDK7. Flavopiridol is initially found to inhibit EGFR and PKA.IC50 Value: ~ 40 nMTarget: CDKin vitro: Flavopiridol induces G1 arrest with inhibition of CDK2 and CDK4 in human breast carcinoma cells in a time and concentration dependent manner. Short time treatment of Flavopiridol (~12 hours) induce apoptosis in hematopoietic cell lines including SUDHL4, SUDHL6 (B-cell lines), Jurkat and MOLT4 (T-cell lines ), and HL60 (myeloid). In the clonogenic assay, Flavopiridol functions as a highly potent cytotoxic compound with a mean IC70 with 8 ng/mL in 23 human tumor models. A recent study shows Flavopiridol treatment induces a substantial AKT-Ser473 phosphorylation in human glioblastoma T98G cell line.in vivo: After treatment with 7.5 mg/kg Flavopiridol bolus intravenous (IV) or intraperitoneal on each of 5 consecutive days, 11 out of 12 advanced stage subcutaneous (s.c.) human HL-60 xenografts undergo complete regressions, and animals remain disease-free several months after one course of Flavopiridol treatment. SUDHL-4 s.c. lymphomas treated with flavopiridol at 7.5 mg/kg bolus IV for 5 days undergo either major (two out of eight mice) or complete (four out of eight mice) regression, with two animals remaining disease-free for more than 60 days. The overall growth delay is 73.2%.

Brivanib alaninate(BMS582664) is an ATP-competitive inhibitor against VEGFR2 with IC50 of 25 nM, moderate potency against VEGFR-1 and FGFR-1, but >240-fold against PDGFR-β.IC50 value: 25 nMTarget: VEGFR2in vitro: Brivanib also inhibits VEGFR1 and FGFR-1 with IC50 of 0.38 μM and 0.148 μM. Brivanib is not sensitive to PDGFRβ, EGFR, LCK, PKCα or JAK-3 with IC50 all above 1900 nM. Brivanib could inhibit the proliferation of VEGF-stimulated HUVECs with IC50 of 40 nM, compared to 276 nM in FGF-stimulated HUVECs. On the other hand, Brivanib exhibits low activity to tumor cell lines [1].in vivo: Brivanib displays antitumor activities in H3396 xenograft in athymic mice. At a dose of 60 and 90 mg/kg (p.o.), Brivanib completely inhibits the tumor growth, with TGI of 85% and 97%, respectively [1]. Moreover, Brivanib significantly suppresses tumor growth in Hepatocellular carcinoma (HCC) xenografts, which due to the decrease in phosphorylation of VEGFR2. The results show that the tumor weights in 06-0606 xenograft mice are 55% and 13%, compared with the controls at a dose of 50 mg/kg and 100 mg/kg. Brivanib is suggested to be efficient in treatment of HCC [2].

SU14813 is an oral, multitargeted tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptors (PDGFR), Kit, and fms-like tyrosine kinase 3 (FLT-3).IC50 value:Target: VEGFR/PDGFR/Flt-3/kitSU14813 was developed as a next-generation TKI agent following sunitinib (SU11248) designed to demonstrate optimized pharmacokinetic (PK) and tolerability profiles. SU14813 demonstrated broad and potent antitumor activity equivalent to that of sunitinib, which resulted in tumor regression, growth arrest, growth delay, and prolonged survival in established xenograft cancer models in mice.

AZM475271 is a potent and selective Src kinase inhibitor with IC50 of 5 nM; no inhibitory activity on Flt3, KDR, Tie-2.IC50 value: 5 nM [1]Target: Src inhibitorin vitro: AZM475271 demonstrated strong dose-dependent inhibition of Src tyrosine kinase activity in the L3.6pl human pancreatic carcinoma cell line. Maximum reduction of Src kinase activity was observed after incubation for 4 hours with ≥5 μmol/L. The IC50 concentration of AZM475271 to inhibit the phosphorylation of c-src, lck, and c-yes was 0.01, 0.03, and 0.08 μmol/L, respectively, in comparison with an IC50 of 0.7 μmol/L AZM475271 to inhibit KDR [2].in vivo: Tumors appeared to be palpable at day 14 after tumor cell injection in all animals except mice treated with both AZM475271 and gemcitabine, in which the earliest possible palpation of the tumors was at day 17 after tumor cell injection. Treatment with gemcitabine or AZM475271 alone did not significantly change animal weight [2].

OSI-930 is a potent inhibitor of Kit, KDR and CSF-1R with IC50 of 80 nM, 9 nM and 15 nM, respectively; also potent to Flt-1, c-Raf and Lck and low activity against PDGFRα/β, Flt-3 and Abl.IC50 value: 9 nM(VEGFR2); 15 nM(CSF1R); 80 nM (Kit activated) [1]Target: VEGFR2/Kit/CSF1Rin vitro: OSI-930 inhibits the cell proliferation in the HMC-1 cell line with IC50 of 14 nM without significant effect on growth of the COLO-205 cell line that does not express a constitutively active mutant receptor tyrosine kinase. Moreover, OSI-930 also induces apoptosis in HMC-1 cell line with EC50 of 34 nM [1]. A recent study shows that OSI-930 inactivates purified, recombinant cytochrome P450 (P450) 3A4 with a Ki of 24 μM in a time- and concentration-dependent mode [2].in vivo: OSI-930, administrated at the maximally efficacious dose of 200 mg/kg by oral gavage, exhibits potent antitumor activity in a broad range of preclinical xenograft models including HMC-1, NCI-SNU-5, COLO-205 and U251 xenograft models [1].

Crenolanib is a potent and selective inhibitor of PDGFRα/β, FLT3 with Kd of 2.1 nM/3.2 nM, 0.74 nM, respectively, sensitive to D842V mutation not V561D mutation, and > 100-fold more selective for PDGFR than c-Kit, VEGFR-2, TIE-2, FGFR-2, EGFR, erbB2, and Src. LY2874455 is a pan-FGFR inhibitor with a similar potency for each enzyme. LY2874455 inhibits FGFR1, 2, 3, and 4 with IC50s of 2.8, 2.6, 6.4, and 6 nM, respectively.Cerdulatinib is a novel, orally available, ATP-competitive inhibitor that demonstrates selective inhibition of SYK and JAK kinases with IC50 of 32 nM for SYK and 0.5-12 nM for JAKs.PF-04979064 is a potent and selective PI3K/mTOR dual kinase inhibitor with an IC(50) of 9.1nM.target：PI3KIC50：9.1nM.PF-04979064 exhibited excellent in vitro potency, very good solubility, high LipE, excellent kinome selectivity,24 robust PK/PD correlation and TGI efficacy, and acceptable predicted human clearance after incorporating both CYP- and AO-mediated metabolism.

NVP-BKM120 Hcl(BKM120) is a selective PI3K inhibitor of p110α/β/δ/γ with IC50 of 52 nM/166 nM/116 nM/262 nM, respectively. Reduced potency against VPS34, mTOR, DNAPK, with little activity to PI4Kβ.IC50 value: 52 nM/166 nM/116 nM/262 nM(p110α/β/δ/γ)[1]Target: p110α/β/δ/γin vitro: BKM120 is not sensitive to Class III and Class IV PI3K's or PI4K. NVP-BKM120 shows great antiproliferation activity to PI3K deregulated cell lines including A2780, U87MG, MCF7 and DU145 with GI50 of 0.1-0.7 nM[1]. BKM120 induces multiple myeloma cells (ARP1, ARK, MM.1S, MM1.R and U266) apoptosis, which results in increased G1-phase cells and decreased S-phase cells. BKM120 induced CD138+ primary MM cell apoptosis and has significant lower cytotoxicity toward CD138- stromal cells. BKM120 exposure could cause upregulation of BimS and downregulation of XIAP[2]. BKM120 demonstrates antiproliferative activity in human gastric cancer cell lines by decreasing mTOR downstream signaling. BKM120 could increase either p-ERK or p-STAT3 in KRAS mutant gastric cancer cells. Combination with STAT3 blockade, BKM120 shows a synergism in cells harboring mutated KRAS by inducing apoptosis, but not in KRAS wild-type cells[3]. in vivo: BKM120 completely inhibits pAktser473 in A2780 xenograft tumors at doses of 30, 60, or 100 mg/kg, respectively. BKM120 also shows antitumor activity against U87MG glioma model at doses of 30 and 60 mg/kg [1]. BKM120 treatment results in significantly reduced tumor volume and level of circulating human kappa chain at 5 μM/kg/day in ARP1 SCID mouse model, with prolonged survival[2].

AZD2932 is a new series of quinazoline ether inhibitor which potently inhibits VEGFR-2 and PDGFR with IC50s of 4 nM/8 nM/ 7 nM for PDGFRβ/VEGFR-2/Flt-3.IC50 value: 4/8/7 nM(PDGFRβ/VEGFR-2/Flt-3) [1]Target: PDGFRβ/VEGFR2The same C6 in vivo model was used to study tumor growth inhibition (TGI) with AZD2932. Twice daily oral dosing (b.i.d.) 10 h apart resulted in significant TGI of 64% for both 50 and 12.5 mg/kg doses on the day the control animals were terminated (day 22 on the graph). Most importantly, xenografts bearing non-PDGFR expressing tumor cells were also sensitive to AZD2932 treatment: growth of Calu-6 tumor was inhibited by 81% and 72% at 50 and 12.5 mg/kg b.i.d. (p <0.001) and LoVo tumors by 67% at 50 mg/kg b.i.d. (p <0.001)[1].

Amuvatinib (MP-470) is a potent and multi-targeted inhibitor of c-Kit, PDGFRα and Flt3 with IC50 of 10 nM, 40 nM and 81 nM, respectively.IC50 Value: 10 nM(c-KitD816H); 40 nM(PDGFRαV561D); 81 nM(Flt3D835Y) [1]Target: c-Kit; PDGFRα; FLT3in vitro: The hydrochloride salt of MP-470 also inhibits several mutants of c-Kit, including c-KitD816V, c-KitD816H, c-KitV560G, and c-KitV654A, as well as a Flt3 mutant (Flt3D835Y) and two PDGFRα mutants (PDGFRαV561D and PDGFRαD842V), with IC50 of 10 nM to 8.4 μM. MP-470 potently inhibits the proliferation of OVCAR-3, A549, NCI-H647, DMS-153, and DMS-114 cells, with IC50 of 0.9 μM–7.86 μM [1]. MP-470 also inhibits c-Kit and PDGFRα, with IC50 values of 31 μM and 27 μM, respectively. MP-470 demonstrates potent cytotoxicity against MiaPaCa-2, PANC-1, and GIST882 cells, with IC50 of 1.6 μM to 3.0 μM. MP-470 also binds to and inhibits several c-Kit mutants, including c-KitK642E, c-KitD816V, and c-KitK642E/D816V [2]. In MDA-MB-231 cells, MP-470 (1 μM) inhibits tyrosine phosphorylation of AXL [3]. In LNCaP and PC-3, but not DU145 cells, MP-470 exhibits cytotoxicity with IC50 of 4 μM and 8 μM, respectively, and induces apoptosis at 10 μM. In LNCaP cells, MP-470 (10 μM) elicits G1 arrest and decreases phosphorylation of Akt and ERK1/2 [4].in vivo: In mice xenograft models of HT-29, A549, and SB-CL2 cells, MP-470 (10 mg/kg–75 mg/kg via i.p. or 50 mg/kg–200 mg/kg via p.o.) inhibits tumor growth [1]. In mice bearing LNCaP xenograft, MP-470 (20 mg/kg) combined with Erlotinib significantly induces tumor growth inhibition (TGI) [4].

Quercitrin is a natural compound found in Tartary buckwheat with a potential anti-inflammation effect that is used to treat heart and vascular conditions.IC50 value:Target:In vitro: There were significant increases in caspase-3 activity, loss of MMP, and increases in the apoptotic cell population in response to quercitrin in DLD-1 colon cancer cells in a time- and dose-dependent manner. [1] In vivo: ICR mice received CCl4 intraperitoneally with or without quercitrin co-administration for 4 weeks. Data showed that quercitrin significantly suppressed the elevation of reactive oxygen species (ROS) production and malondialdehyde (MDA) content, reduced tissue plasminogen activator (t-PA) activity, enhanced the antioxidant enzyme activities and abrogated cytochrome P450 2E1 (CYP2E1) induction in mouse brains. [2]

PI3K inhibitor X is a derivative compound discovered by Exelixis Inc. But we cannot find more biological information. IC50 value:Target: PI3KXL147, another PI3K inhibitor, now is in clinical status. They have similar chemical structure and may be have the same mechanism. For more information, you can refer to the two patents, WO 2012065057 and WO 2012006552.

AZD-3463 is an ALK/IGF1R inhibitor which overcomes multiple mechanisms of acquired resistance to crizotinib.IC50 Value:Target: ALK/IGF1R

Cediranib is a highly potent VEGFR(KDR) inhibitor with IC50 of <1 nM, and also inhibits Flt1/4 with IC50 of 5 nM/≤3 nM, with similar activity against c-Kit and PDGFRβ, 36-, 110-fold and is >1000-fold selective more for VEGFR than PDGFR-α, CSF-1R and Flt3.AZ628 is a new pan-Raf inhibitor for BRAF, BRAFV600E, and c-Raf-1 with IC50 of 105 nM, 34 nM and 29 nM, also inhibits VEGFR2, DDR2, Lyn, Flt1, FMS, etc.IC50 value: 105 nM/34 nM/29 nM (BRAF/BRAFV600E/c-Raf-1) [1]Target: pan-Rafin vitro: others. AZ628 suppresses anchorage-dependent and -independent growth, gives rise to cell cycle arrest, and induces apoptosis in colon and melanoma cell lines harboring B-RafV600E mutation. The profile of AZ628 cross-reactivity suggests that similar to sorafenib, AZ628 may be antiangiogenic based on prevention of VEGFR2 [1]. AZ628-resistant clones are approximately 100-fold more resistant to AZ628 than the parental cell line, exhibiting IC50 of approximately 10 μM, compared with 0.1 μM for the parental cell line. Effective suppression of p-ERK1/2 levels is observed in the M14 parental cell line following treatment with increasing concentrations of AZ628. AZ628-resistant clones express elevated CRAF. Elevated CRAF expression is a potential mechanism of acquired resistance to continuous AZ628 exposure, resulting in sustained activation of ERK1/2. p-ERK1/2 activity is not significantly inhibited by exposure to AZ628 in one of these three AZ628-insensitive cell lines (Wm1552C). Unlike in the AZ628-resistant M14 cells in which AZ628 fails to suppress the activation of ERK, AZ628 treatment efficiently attenuates ERK activation in the NRAS mutant melanoma cells [2].

AZD2858 is a selective GSK-3 inhibitor with an IC50 of 68 nM, inhibits tau phosphorylation at the S396 site, activates Wnt signaling pathway.IC50 Value: 68 nM [1]Target: GSK3in vitro: Treatment (1 μM) of human osteoblast cells with AZD2858 in vitro increased β-catenin levels after a short period of time. AZD2858 treatment (1 μM, 12 h) on primary isolated human osteoblast-like cells results in a 3-fold increase of β-catenin levels [1].in vivo: In rats, oral AZD2858 treatment caused a dose-dependent increase in trabecular bone mass compared to control after a two-week treatment with a maximum effect at a dose of 20 mg/kg once daily (total BMC: 172% of control; p<0.001). A small but significant effect was also seen at cortical sites (total BMC: 111% of control; p<0.001). Biomechanical testing demonstrated an increase in both vertebral compression strength at a dose of 20 mg/kg once daily (Load at failure: 370% of control, p<0.001) and diaphyseal strength of femora subjected to a three point bending test (Load at failure: 115% of control; p<0.01) [1]. The rats were treated with oral administration of AZD2858 at a dose of 30 μmol/kg (20mg/kg) daily for up to 3 weeks, while control animals were administered vehicle. At 4days, and at 1, 2 and 3 weeks, histological analysis was performed, and at the 2 and 3 week time points, we performed peripheral quantitative computed tomography (pQCT), X-rays, and four-point bending tests [2].Toxicity: Clinical trial:

SB-590885 is a potent B-Raf inhibitor with Ki of 0.16 nM, and has 11-fold greater selectivity for B-Raf over c-Raf, without inhibition to other human kinases.ONO-4059 is a highly selective, orally bioavailable BTK inhibitor with a potency (IC50) of 2.2 nM. target: BTK IC:50 2.2 nM [1] In vitro: The compound covalently bonds to BTK, inhibiting BCR signaling and B-cell proliferation and activation. [1] NO/GS-4059 induced durable responses in relapsed/refractory B-cell malignancies without significant toxicities.[2]In vivo: ONO-4059 demonstrated therapeutic efficacy in a mouse arthritis model, and based on its anti-proliferative activity in B-cells. [1]

Tivozanib (AV-951) is a potent and selective VEGFR inhibitor for VEGFR1/2/3 with IC50 of 30 nM/6.5 nM/15 nM, and also inhibits PDGFR and c-Kit, low activity observed against FGFR-1, Flt3, c-Met, EGFR and IGF-1R.IC50 value: 30 nM/6.5 nM/15 nM(VEGFR1/2/3) [1]Target: VEGFR1/2/3in vitro: AV-951 is a novel quinoline-urea derivative. AV-951 blocks VEGF-dependent activation of mitogen-activated protein kinases and proliferation of endothelial cells [1]. In vivo studies show that AV-951 also decreases the micro vessel density and suppresses VEGFR2 phosphorylation levels in tumor xenografts, especially at a concentration of 1mg/kg (p.o. administration). AV-951 shows almost complete inhibition of tumor xenografts growth (TGI>85%) in athymic rats [1]. Another study in rat peritoneal disseminated tumor model shows that AV-951 could prolong the survival of the tumor-bearing rats with the MST of 53.5 days. AV-951 displays antitumor activity against many human tumor xenografts including lung, breast, colon, ovarian, pancreas and prostate cancer [2].

SGI-7079 is an Axl inhibitor, significantly inhibits the proliferation of SUM149 or KPL-4 cells with an IC50 of 0.43 or 0.16 μM, respectively.Ic50 value:Target: Axlin vitro: SGI-7079 treatment inhibits the phosphorylation of Axl at Tyr 702 upon Gas6 stimulation in SUM149 cells. The growth of SUM149 and KPL-4 in soft agar, one of the hallmark characteristics of cellular transformation and uncontrolled cell growth, is also significantly inhibited by SGI-7079 treatment. SGI-7079 treatment also significantly decreases the migration and invasion of SUM149 cells and the invasion of KPL-4 cells. Taken together, Axl inhibitor SGI-7079 significantly inhibits the proliferation, migration, and invasion of IBC cells, suggesting that Axl may be a promising therapeutic target in patients with IBC. [1]in vivo: SGI-7079 inhibits tumor growth in a dose dependent manner, and at the maximum dose, inhibited tumor growth by 67%, compared to control. The combined inhibition of Axl (SGI-7079) plus EGFR (Erlotinib) is significantly more effective than either drug alone. Notably, SGI-7079 + Erlotinib (25/100 mg/kg) reduced the tumor growth by 82%. Axl blockade by SGI-7079 inhibits the growth of mesenchymal NSCLC xenograft tumors. [2]

GDC-0623 is a potent, ATP-uncompetitive inhibitor of MEK1 (Ki=0.13 nM, +ATP), and displays 6-fold weaker potency against HCT116 (KRAS (G13D), EC50=42 nM) versus A375 (BRAFV600E, EC50=7 nM).The product is the analog of ONO-4059, ONO-4059 is a highly potent and selective Btk inhibitor with an IC50 in the sub-nM range. IC50 value: sub-nM range [2]Target: Btkin vitro: ONO-4059 ( analog ) is a selective, once-daily, oral inhibitor of BTK, which has been shown to play a role in the survival and proliferation of malignant B-cells. ONO-4059 (analog) shows a favourable safety profile along with promising efficacy in this difficult-to-treat patient population. [1]in vivo: ONO-4059 (analog) has demonstrated anti-tumour activity in several pre-clinical models.[1] ONO-4059 (analog) potently and dose-dependently reverse clinical arthritis and prevented bone damage in the CIA model.[2]

AZD8186 is an isoform-specific small-molecule PI3K inhibitor, potently inhibits PI3Kβ (IC50=4 nM) and PI3Kδ (IC50=12 nM) with selectivity over PI3Kα (IC50=35 nM) and PI3Kγ (IC50=675 nM).IC50 value: 4 nM (PI3Kβ), 12 nM (PI3Kδ)Target: PI3Kin vitro: AZD8186 selectively inhibits PI3Kβ- and δ-mediated signaling through AKT. AZD8186 inhibits PI3Kβ-dependent activation of pAKT (Ser473) with an IC50 value of 3 nM in the PTEN-null line MDA-MB-468. AZD8186 inhibits IgM-stimulated phosphorylation of pAKT (Ser473) activation in JEKO cells with an IC50 value of 17 nM. In cell proliferation assays, AZD8186 inhibits proliferation of MDA-MB-468 cells with a GI50 value of 65 nM, IgM stimulated JEKO cell growth with an IC50 value of 228 nM. It only inhibits BT474c cell growth with an IC50 value of 1.981 μM consistent with its selectivity for PI3Kβ over PI3Kα.in vivo: AZD8186 modulates pathway biomarkers and inhibits growth of breast and prostate tumor models. In mouse, AZD8186 has a short half-life delivering a PK profile that results in intermittent cover over a 24 hours dosing interval. AZD8186 selectively modulates AKT activation in PTEN-null tumor tissues.

AS 602801 is an ATP-competitive JNK inhibitor with IC50 of 80 nM, 90 nM, and 230 nM for JNK1, JNK2, and JNK3, respectively.Selumetinib is a highly potent MEK inhibitor, with an IC50 value of 14 nM against MEK1.

GDC-0032 is a potent β-sparing small molecule inhibitor of PI3K, with IC50 values of 0.29 nM, 0.91 nM, 0.97 nM for PI3Kα, PI3Kβ and PI3Kγ, respectively.

AZD0156 is an orally active, potent and selective ATM kinase inhibitor, used for cancer treatment.

GSK2334470 is a highly specific and potent inhibitor of PDK1 with an IC50 of 10 nM.

VE-822 is an ATR inhibitor with Ki value of <0.2 nM, also inhibits ATM with Ki of 34 nM.

BI-847325 is an ATP competitive dual inhibitor of MEK and aurora kinases (AK) with IC50 values of 4 and 15 nM for human MEK2 and AK-C, respectively.Tozasertib is the inhibitor of Aurora-A, -B, -C kinases with Ki values of 0.6, 18, 4.6 nM, respectively.

Sorafenib is a potent multikinase inhibitor with IC50s of 6 nM, 20 nM, and 22 nM for Raf-1, B-Raf, and VEGFR-3, respectively.

Acalabrutinib is a novel, potent, and highly selective BTK inhibitor, with an IC50 of 3 nM and EC50 of 8 nM in a human whole-blood CD69 B cell activation assay.

YM-201636 is a potent and selective PIKfyve inhibitor with an IC50 of 33 nM.

NVP-TAE 226 is a dual tyrosine kinase inhibitor of FAK (IC50=5.5 nM) and IGF-IR (mean IC50=0.14 μM).

GDC-0068 is a highly selective pan-Akt inhibitor targeting Akt1/2/3 with IC50 of 5/18/8 nM, 620-fold selectivity over PKA. AZD3759 is a potent, oral active, central nervous system-penetrant, EGFR inhibitor. At Km ATP concentrations, the IC50s are 0.3, 0.2, and 0.2 nM for EGFRwt, EGFRL858R, and EGFRexon 19Del, respectively.NVP-LCQ195 (AT9311; LCQ195) is a small molecule heterocyclic inhibitor of CDK1, CDK2, CDK3 and CDK5 with IC50 of 1-42 nM.IC50 Value: 1 nM(CDK5/p25 and CDK5/p35); 2 nM(CDK1/cyclinB and CDK2/cyclinA); 5 nM(CDK2/cyclinE); 42 nM(CDK3/cyclinE)Target: CDKsLCQ195 induced cell cycle arrest and eventual apoptotic cell death of MM cells, even at sub-lmol/l concentrations, spared non-malignant cells, and overcame the protection conferred to MM cells by stroma or cytokines of the bone marrow milieu. In MM cells, LCQ195 triggered decreased amplitude of transcriptional signatures associated with oncogenesis, drug resistance and stem cell renewal, including signatures of activation of key transcription factors for MM cells e.g. myc, HIF-1a, IRF4. Bortezomib-treated MM patients whose tumours had high baseline expression of genes suppressed byLCQ195 had significantly shorter progression-free and overall survival than those with low levels of these transcripts in their MM cells. These observations provide insight into the biological relevance of multi-targeted CDK inhibition in MM.

PHA-848125(Milciclib) is a potent, ATP-competitive CDK inhibitor for CDK2 with IC50 of 45 nM; >3-fold more selective for CDK2 than CDK1, 2, 4, 5, and 7.IC50 Value: 45 nMTarget: CDK2in vitro: PHA-848125 inhibits, although with lower potency, the activities of cyclin H/CDK7, cyclin D1/CDK4, p35/CDK5, as well as cyclin E/CDK2 and cyclin B/CDK1 with IC50 values of 0.15, 0.16, 0.265, 0.363, 0.398 μM, respectively. PHA-848125 also impairs phosphorylation of the retinoblastoma protein at CDK2 and CDK4 specific sites, reduces retinoblastoma protein and cyclin A levels, and increases p21(Cip1), p27(Kip1) and p53 expression. PHA-848125 is added to the cells 48 h after TMZ and cell growth is evaluated after 3 additional days of culture. A drug combination of TMZ, BG and PHA-848125 induces an additive or synergistic effect on cell growth, depending on the cell line. in vivo: In the preclinical xenograft A2780 human ovarian carcinoma model, PHA-848125 reveals good efficacy and is well tolerated upon repeated daily treatments. Treatment of K-Ras(G12D)LA2 mice with PHA-848125 (40 mg/kg twice daily for 10 days) results in significant tumor growth inhibition at the end of the treatment and is accompanied by a reduction in the cell membrane turnover. On the other hand, following oral administration, PHA-848125 shows significant antitumor activity in various human xenografts, carcinogen-induced tumors and in disseminated primary leukemia models; the plasma concentrations in rodents being in the same range as those found inhibiting cancer cell proliferation.

AZD8330(ARRY-424704; ARRY-704) is a novel, selective, non-ATP competitive MEK 1/2 inhibitor with IC50 of 7 nM.IC50 value: 7 nM [1]Target: MEK1/2in vitro: AZD8330 potently and strongly inhibits MEK 1/2. AZD8330 has no inhibitory activity against over 200 other kinases including at concentrations up to 10 μM. AZD8330 demonstrates sub-nanomolar potency in mechanistic (pERK) and low to sub-nanomolar potency in functional (proliferation) assays in MEK 1/2 inhibitor sensitive cell lines. in vivo: In a Calu-6 rat xenograft pharmacokinetic/pharmacodynamic (PK/PD) model a single, 1.25 mg/kg oral dose of AZD8330 inhibits ERK phosphorylation by > 90% for between 4 and 8 hours. Doses as low as 0.4 mg/kg once daily are sufficient for > 80% tumor growth inhibition in the Calu-6 nude rat xenograft model. In the Calu-6 model, AZD8330 inhibits tumor growth in a dose-dependent fashion, at 0.3 mg/kg and 1.0 mg/kg once daily.

Necrosulfonamide is a pharmacological inhibitor of MLKL with IC50 values of 124 nM in human HT-29.target: MLKL[1]IC50 : 124 nM.In vitro: Necrosulfonamide significantly decreases BV6/DAC-induced cell death in MV4-11 cells.[1] Treating cells with necrosulfonamide or knocking down MLKL expression arrests necrosis at a specific step at which RIP3 formed discrete punctae in cells. necrosulfonamide had no effect on apoptosis induced by TNF-α plus Smac mimetic in non-RIP3-expressing Panc-1 cells.[2] Complete inhibition was observed at NSA concentration of 0.5 M. NSA is also an effective inhibitor of the necroptotic pathway induced by STS in the presence of caspase inhibitor. [3]BMS-754807 is a potent and reversible inhibitor of the insulin-like growth factor 1 receptor (IGF-1R)/insulin receptor family kinases (IR) with IC50 of 1.8 and 1.7 nM, respectively and Ki of <2 nM for both, and also shows potent activities against Met, RON, TrkA, TrkB, AurA, and AurB with IC50 values of 6, 44, 7, 4, 9, and 25 nM, respectively. Perifosine is an oral Akt inhibitor. All cells are sensitive to the antiproliferative properties of Perifosine with an IC50 of ~0.6-8.9 μM.

MK-5108 is a highly potent and specific inhibitor of Aurora-A kinase with an IC50 value of 0.064 nM.

CX-6258 is a potent, orally efficacious Pim 1/2/3 kinase(IC50=5 nM/25 nM/16 nM) inhibitor with excellent biochemical potency and kinase selectivity.IC50 Value: 5 nM/25 nM/16 nM (Pim 1/2/3) [1]Target: pan-Pimin vitro: CX-6258 inhibited Flt-3 and Pim-3 (IC50=0.134 and 0.016 uM). At 0.5 uM of CX-6258, only Pim-1, Pim-2, Pim-3, and Flt-3 of the 107 kinases tested were inhibited by more than 80%, showing excellent selectivity. CX-6258 was also shown to be a reversible inhibitor of Pim-1 (Ki=0.005 uM). CX-6258 showed robust antiproliferative potencies against all cell lines tested derived from human solid tumors and hematological malignancies. In mechanistic cellular assays with MV-4-11 human AML cells, (13) caused dose-dependent inhibition of the phosphorylation of 2 pro-survival proteins, Bad and 4E-BP1, at the Pim kinase specific sites S112 and S65 and T37/46, respectively[1]. Pim-1 inhibition using the small molecule inhibitor CX-6258 (12 mM, 3 h) diminishes endogenous NKX3.1 steady state levels in 22RV1 and LNCaP cells. CX-6258 treatment (12 mM, 3 h) treatment diminished steady-state levels of ectopic NKX3.1 in PC3 cells. CX-6258 treatment resulted in a significant reduction in NKX3.1 half-life. While ectopically expressed NKX3.1 in control cells had a half-life of _90 min, Pim-1 inhibition reduced the half-life to _52 min [2].in vivo: CX-6258 showed dose-dependent efficacy in mice bearing MV-4-11 xenografts, with 45% and 75% TGI at 50 and 100 mg/kg/day, respectively. Treatment of mice bearing PC3 xenografts with CX-6258 p.o. 50 mg/kg was also well tolerated and produced 51% TGI.

Sal003 is a potent cell-permeable analog of the eIF2α phosphatase inhibitor Salubrinal with enhanced aqueous solubility.IC50 value:Target: eIF2α phosphatase inhibitorSal003 has been shown to prevent dephosphorylation of eIF-2α which has been shown to regulate the late phase of long-term potentiation (LTP) and memory (LTM). This enhanced phosphorylated state of eIF-2α is shown to prevent L-LTP and suppress memory in mice.BAY 61-3606 (dihydrochloride) is a potent, ATP-competitive, reversible, and highly selective inhibitor of Syk tyrosine kinase (IC50=10 nM) with no inhibitory effect on Btk, Fyn, Itk, Lyn, and Src.

AMG-337 is a potent and highly selective small molecule ATP-competitive MET kinase inhibitor. AMG 337 inhibits MET kinase activity with an IC50 of < 5nM in enzymatic assays.IC50 value: < 5nM [1]Target: METin vitro: AMG-337 demonstrates exquisite selectivity for MET when profiled against a diverse panel of over 400 protein and lipid kinases in a competitive binding assay. In cellular assays, AMG 337 inhibits HGF-dependent MET phosphorylation with an IC50 of < 10 nM. [1] AMG 337 is a selective inhibitor of Met, which inhibits multiple mechanisms of Met activation. [2]in vivo: AMG-337 demonstrates robust activity in MET-dependent cancer models. Oral administration of AMG 337 results in robust dose-dependent anti-tumor efficacy in MET amplified gastric cancer xenograft models, with inhibition of tumor growth consistent with the pharmacodynamic modulation of MET signaling.[1]AZD4547 is a potent inhibitor of the FGFR family with IC50 of 0.2 nM, 2.5 nM, 1.8 nM, and 165 nM for FGFR1, FGFR2, FGFR3, and FGFR4, respectively.UNC2881 is a potent and specific Mer kinase inhibitor; inhibits steady-state Mer kinase phosphorylation with an IC50 value of 22 nM. IC50 value: 22 nM [1]Target: Mer kinase inhibitorTreatment with UNC2281 is also sufficient to block EGF-mediated stimulation of a chimeric receptor containing the intracellular domain of Mer fused to the extracellular domain of EGFR. In addition, UNC2881 potently inhibits collagen-induced platelet aggregation, suggesting that this class of inhibitors may have utility for prevention and/or treatment of pathologic thrombosis.

Afuresertib hydrochloride is an orally available, ATP-competitive, pan-AKT inhibitor with Ki of 0.08, 2 and 2.6 nM against AKT1, AKT2 and AKT3, respectively.

MRT67307 is a dual inhibitor of the IKKε and TBK-1, which mediates the phosphorylation of interferon regulatory factor 3 (IRF3), with IC50 values of 160 and 19 nM when assayed at 0.1 mM ATP in vitro, and also targets ULK1 and ULK2 with high potency (IC50 values of 45 and 38 nM, respectively).

CHIR-99021 is a GSK-3α/β inhibitor with IC50 of 10 nM/6.7 nM; > 500-fold selectivity for GSK-3 versus its closest homologs CDC2 and ERK2, as well as other protein kinases. JI-101 is an oral multi-kinase inhibitor that targets vascular endothelial growth factor receptor type 2 (VEGFR-2), platelet derived growth factor receptor β (PDGFR-β), and ephrin type-B receptor 4 (EphB4). JI-101 inhibits angiogenesis, and subsequently tumor growth. [1]In vitro :Caco-2 human intestinal epithelial cells were plated in 24-Transwell dual chamber plates (cell density of 500 000 cells/cm2 on day-1). The permeability studies were conducted with the monolayers cultured for 20-23 days in culture. The integrity of each Caco-2 cell monolayer was certified by trans-epithelial electrical resistance (TEER) test (pre-experiment) and by determining the permeability of reference compounds3H-propranolol (high permeability) and 3H-mannitol (low permeability). In addition, the reference substrate 3H-vinblastine was included as a positive control P-gp substrate. The concentration of JI-101 used in the assay was 10 and 100 uM. All the stocks were made in DMSO and the final concentration of DMSO in spiking solution was 0.5%. [2]in vivo: For oral administration JI-101 was formulated as a suspension with 20 μL of Tween-80 and 0.5% methyl cellulose. Pharmacokinetics and bioavailability assessment of JI-101 were evaluated in a preliminary parallel-group study in male S.D. rats. Four rats (195-210 g) per route received JI-101 at a dose of 3 and 30 mg/kg for i.v. (via tail vein) and oral dose (by gavage), respectively.[2]

Pelitinib (EKB-569; WAY-EKB 569) is a potent irreversible EGFR inhibitor with IC50 of 38.5 nM.IC50 value: 38.5 nM [1]Target: EGFRin vitro: Pelitinib displays much higher inhibitory activity against EGFR, compared with the closely related c-erbB-2, as well as other kinases such as Src, Cdk4, c-Met, Raf, and MEK/ERK, with IC50 ranging from 282 nM for Src to >20 μM for Cdk4. Consistently, Pelitinib treatment significantly inhibits the autophosphorylation of EGFR but not c-Met in A431 cells [1]. Pelitinib potently inhibits the proliferation of normal human keratinocytes (NHEK), as well as A431 and MDA-468 tumor cells with IC50 of 61 nM, 125 nM, and 260 nM, respectively, while displaying little activity against MCF-7 cells with IC50 of 3.6 μM. Pelitinib inhibits EGF-induced phosphorylation of EGFR in A431 and NHEK cells with IC50 of 20-80 nM, as well as the phosphorylation of STAT3 with IC50 of 30-70 nM. Pelitinib at 75-500 nM also specifically inhibits the activation of AKT and ERK1/2, without affecting NF-κB pathway. In NHEK cells, Pelitinib also potently inhibits TGF-α mediated EGFR activation with IC50 of 56 nM, as well as activation of STAT3 and ERK1/2 with IC50 of 60 nM and 62 nM, respectively [2]. in vivo: A single oral dose of 10 mg/kg Pelitinib potently inhibits the EGFR phosphorylation in A431 xenografts with over-expressed EGFR, by 90% within 1 hour, and by >50% after 24 hours. Administration of Pelitinib at 20 mg/kg/day inhibits tumorigenesis in APCMin/+ mice by 87%, equivalent to the effect of used with 2 times doses of EKI-785 (40 mg/kg/day), consistent with greater in vivo potency [1]. Pelitinib selectively inhibits EGFR signaling in airway epithelial cells in vivo. In the mouse model of airway epithelial remodeling that is inducible by viral infection and features a delayed but permanent switch to goblet cell metaplasia, Pelitinib treatment at 20 mg/kg/day corrects all 3 aspects of epithelial remodeling, by completely blocking the increase of ciliated cells and decrease of Clara cells, and significantly inhibiting the metaplasia of goblet cells [3].

Mubritinib(TAK-165) is a potent and selective inhibitor of HER2/ErbB2 with IC50 of 6 nM; with no inhibition on EGFR, FGFR, PDGFR etc.IC50 value: 6 nM [1]Target: HER2 inhibitorin vitro: Mubritinib displays > 4000-fold selectivity over other tyrosine kinases, such as EGFR, FGFR, PDGFR, Jak1, Src and Blk. Mubritinib even at low concentration of 0.1 μM significantly blocks HER2 phosphorylation, leading to the downregulation of PI3K-Akt and MAPK pathway in cell line BT474 with high level of HER2. Mubritinib not only exhibits highly potent antiproliferative effect in ErbB2-overexpressing cancer cell line BT474 with an IC50 of 5 nM, but also displays marked antiproliferative effects in cell lines with HER2 expressed weakly with IC50 of 53 nM, 90 nM and 91 nM for LNCaP, LN-REC4 and T24, respectively. Mubritinib displays no inhibitory activities against PC-3 cells with HER2 expressed very faintly with IC50 of 4.62 μM, as well as EGFR-overexpressing HT1376 and ACHN cell lines with IC50 of >25 μM [1].in vivo: Mubritinib significantly inhibits LN-REC4 xenograft with treatment/control tumor volume ratio of 26.5%. Although ineffective to inhibit the growth of UMUC-3 and ACHN cells in vitro (IC50s of 1.812 and >25 μM, respectively), oral administration of Mubritinib (10 or 20 mg/kg per day) significantly inhibits the growth of UMUC-3 and ACHN xenografts with treatment/control tumor volume ratio of 22.9% and 26%, respectively, as compared with Herceptin (20 mg/kg) which is ineffective to UMUC-3 tumor growth [1].

PF-04217903 methanesulfonate is a selective ATP-competitive c-Met inhibitor with IC50 of 4.8 nM, susceptible to oncogenic mutations (no activity to Y1230C mutant).IC50 value: 4.8 nM [1]Target: c-Metin vitro: Being more selective than staurosporine or PF-02341066, PF-04217903 displays >1000-fold selectivity for c-Met over a panel of 208 kinases, although more susceptible to oncogenic mutations of c-Met that attenuate potency than PF-02341066. In addition to WT c-Met, PF-04217903 displays similar potency to inhibit the activity of c-Met-H1094R, c-Met-R988C, and c-Met-T1010I with IC50 of 3.1 nM, 6.4 nM, and 6.7 nM, respectively, but has no inhibitory activity against c-Met-Y1230C with IC50 of >10 μM [1]. PF-04217903 in combination with sunitinib significantly inhibits endothelial cells, but not the tumor cells B16F1, Tib6, EL4, and LLC [2] PF-04217903 significantly inhibits the clonogenic growth of LXFA 526L and LXFA 1647L with IC50 values of 16 nM, and 13 nM, respectively, yielding an additive effect when in combination with cetuximab [3]. in vivo: Although unable to inhibit tumor growth in the sunitinib-sensitive B16F1 and Tib6 tumor models, the combination of PF-04217903 and sunitinib significantly inhibits tumor growth in sunitinib-resistant EL4, and LLC tumor models compared with sunitinib or PF-04217903 alone by significantly blocking vascular expansion, indicating a functional role for HGF/c-Met axis in the sunitinib-resistant tumors [2].

HTH-01-015 is a potent and selective inhibitor of NUAK1 with IC50 of 100 nM, does not significantly inhibit NUAK2 (IC50 of >10 μM).IC50 value: 100 nM [1]Target: NUAK1HTH-01-015 did not markedly suppress the activity of any of the other 139 protein kinases evaluated. Treatment of cells with 10 μM HTH-01-015, the NUAK1 isoform selective inhibitor, only led to a partial inhibition of MYPT1 phosphorylation. In HEK-293 cells expressing wild-type NUAK1, concentrations of 3–10 μM WZ4003 or HTH-01-015 markedly suppressed phosphorylation of MYPT1.

BMS-794833 is a potent ATP competitive inhibitor of Met/VEGFR2 with IC50 of 1.7/15 nM; also inhibits Ron, Axl and Flt3 with IC50 of <3 nM; a prodrug of BMS-817378.IC50 value: 1.7/15 nM [1]Target: Met/VEGFR2BMS794833 also inhibits Met receptor activated gastric carcinoma cell line, GTL-16, with IC50 of 39 nM. In GTL-16 human gastric tumor xenografts model, BMS798433 shows greater than 50% TGI for at least one tumor doubling time with no overt toxicity observed during 14 days. BMS798433 also shows complete tumor stasis at a dose of 25 mg/kg against U87 glioblastoma model.

Ki8751 is a potent and selective inhibitor of VEGFR2 with IC50 of 0.9 nM, >40-fold selective for VEGFR2 than c-Kit, PDGFRα and FGFR-2, little activity to EGFR, HGFR and InsR.IC50 value: 0.9 nM [1]Target: VEGFR2in vitro: Ki8751 potently and selectively inhibits VEGFR2 with IC50 of 0.9 nM. Ki8751 also inhibits PDGFRα, c-Kit, and FGFR-2, with much higher IC50 values (40 nM–170 nM). Except for these several kinases, Ki8751 doesn't disturb other kinases, including HGFR, EGFR, and InsulinR, even at 10 μM [1]. In human umbilical vein endothelial cells (HUVECs), Ki8751 (1 nM–100 nM) effectively decreases VEGF-stimulated cell proliferation and vasculature permeability [2]. In metastatic colorectal cancer (CRC) cells MIP, RKO, SW620, and SW480, but not in HCT116, Ki8751 (10 nM) increases cellular senescence [3].in vivo: In nude mice bearing human tumor xenografts of GL07, St-4, LC6, DLD-1, and A375 cells, Ki8751 (20 mg/kg) inhibits tumor growth. In nude rat xenograft models of LC-6 cells, Ki8751 (5 mg/kg) completely inhibits tumor growth without affecting body weight [1].

CP-724,714 is a potent, selective inhibitor of HER2/ErbB2 with IC50 of 10 nM, >640-fold selectivity against EGFR, InsR, IRG-1R, PDGFR, VEGFR2, Abl, Src, c-Met etc. Phase 2.IC50 value: 10 nM [1]Target: HER2/ErbB2in vitro: CP-724,714 is marked selectively against EGFR with IC50 of 6.4 μM. CP-724,714 is >1,000-fold less potent for IR, IGF-1R, PDGFRβ, VGFR2, abl. Src, c-Met c-jun NH2-terminal kinase (JNK)-2, JNK-3, ZAP-70, cyclin-dependent kinase (CDK)-2, and CDK-5. CP-724,714 potently reduces the EGF-induced autophosphorylation of the chimera containing the erbB2 kinase domain with IC50 of 32 nM, but is markedly less potent against EGFR in transfected NIH3T3 cells. CP-724,714 sensitively inhibits the proliferation of erbB2-amplified cells including BT-474 and SKBR3, with IC50 of 0.25 and 0.95 μM. CP-724,714 induces the accumulation of cells in G1 phase and a marked reduction in S-phase in BT-474 cells at 1 μM [1]. CP-724,714 likely exerts its hepatotoxicity via both hepatocellular injury and hepatobiliary cholestatic mechanisms. CP-724,714 displays inhibition of cholyl-lysyl fluorescein and taurocholate (TC) efflux into canaliculi in cryopreserved and fresh cultured human hepatocytes, respectively. CP-724,714 inhibits TC transport in membrane vesicles expressing human bile salt export pump with IC50 of 16 μM and inhibits the major efflux transporter in bile canaliculi, MDR1, with IC50 of ~28 μM [2]. in vivo: CP-724,714 (25 mg/kg) is rapidly absorbed after p.o. administration and causes reduction of tumor erbB2 receptor phosphorylation after dosing in FRE-erbB2 or BT-474 xenografts. CP-724,714 induces apoptosis in FRE-erbB2 xenograft–bearing (s.c.) mice and shows 50% tumor growth inhibition at 50 mg/kg, without weight loss or mortality. CP-724,714 also has great antitumor activity in MDA-MB-453, MDA-MB-231, LoVo (colon), and Colo-205 (colon) xenografts. Furthermore, CP-724,714 (30 or 100 mg/kg) reduces the extracellular signal–regulated kinase and Akt phosphorylation in BT-474 xenografts [1].

AZD8835 is a potent and selective inhibitor of PI3Kδ and PI3Kαwith IC50 of 5.7 nM and 6.2 nM, with selectivity against PI3Kβ (IC50 431 nM) and PI3Kγ (IC50 90 nM).IC50 value: 5.7 nM (PI3Kδ), 6.2 nM (PI3Kα)Target: PI3Kin vitro: AZD8835 is a orally bioavailable inhibitor of the class I (PI3K) catalytic subunit alpha (PIK3CA), with potential antineoplastic activity. PI3K alpha inhibitor AZD8835 selectively binds to and inhibits PIK3CA and its mutated forms, in the PI3K/Akt (protein kinase B)/mammalian target of rapamycin (mTOR) pathway. This results in both apoptosis and growth inhibition in PIK3CA-expressing tumor cells. By specifically targeting PIK3CA, this agent may be more efficacious and less toxic than pan-PI3K inhibitors. Dysregulation of the PI3K/Akt/mTOR pathway is often found in solid tumors and results in the promotion of tumor cell growth, survival, and resistance to chemo- and radio-therapy. PIK3CA, one of the most frequently mutated oncogenes, encodes the p110-alpha catalytic subunit of the class I PI3K.In vivo: AZD8835 shows pharmacodynamic modulation of AKT phosphorylation and near complete inhibition of tumour growth (93% tumour growth inhibition) in a murine H1047R PI3Kalpha mutated SKOV-3 xenograft tumour model after chronic oral administration at 25 mg/kg b.i.d.

Dacomitinib is a specific and irreversible inhibitor of the ERBB family of kinases with IC50 of 6 nM, 45.7 nM and 73.7 nM for EGFR, ERBB2, and ERBB4, respectively.LY2784544 is a potent JAK2 inhibitor with IC50 of 3 nM. LY2784544 also inhibits FLT3, FLT4, FGFR2, TYK2, and TRKB with IC50 of 4, 25, 32, 44, and 95 nM.

R406 is a potent Syk inhibitor with IC50 of 41 nM, strongly inhibits Syk but not Lyn, 5-fold less potent to Flt3. IC50 value: 41 nM [1]Target: Syk in vitro: R406 is a potent inhibitor of immunoglobulin E (IgE)- and IgG-mediated activation of Fc receptor signaling. R406 inhibits the anti-IgE-induced production and release of LTC4 and cytokines and chemokines, including TNFα, IL-8, and GM-CSF. R406 inhibits phosphorylation of Syk substrate linker for activation of T cells in mast cells and B-cell linker protein/SLP65 in B cells. R406 binds to the ATP binding pocket of Syk and inhibits its kinase activity as an ATP-competitive inhibitor with Ki of 30 nM. R406 blocks Syk-dependent FcR-mediated activation of monocytes/macrophages and neutrophils and Bcr-mediated activation of B lymphocytes [1]. R406 significantly induces chronic lymphocytic leukemia (CLL) cell apoptosis in nurselike cells cocultures and blocks CCL3 and CCL4 secretion by CLL cells in response to B-cell antigen receptor (Bcr) triggering [2]. R406 is a potent inhibitor of platelet signaling and functions initiated by FcγRIIA cross-linking by specific antibodies or by sera from HIT patients [3].in vivo: R406 reduces cutaneous reverse passive Arthus reaction by approximately 86% at 5 mg/kg in prophylactic treated mice. R406 also shows efficacy in inhibiting paw inflammation in antibody-induced arthritis mouse models [1]. R406 does not adversely affect macrophage or neutrophil function in innate immune responses and has minimal functional immunotoxicity notwithstanding its lymphocytopenic effect [4].

ETP-46464 is a cell-permeable quinoline-containing heterotricyclic compound that acts as a potent inhibitor against mTOR, ATR, DNA-PK, PI 3-Kα, and ATM (IC50= 0.6, 14, 36, 170, and 545 nM, respectively).IC50 Value: 0.6 nM (mTOR); 14 nM (ATR) [1]Target: ATR; mTORETP-46464 preferentially suppresses radiation-induced cellular ATR activity (>90% at 500 nM) over ATM or DNA-PK activity (IC50 > 5 uM) in U2OS cells, while exhibiting much reduced or little potency toward a panel of 26 other kinases (>55% inhibition at 5 uM). ETP-46464 is Shown to synergize with UCN-01 in replicative stress induction in S-phase replicating U2OS (1.5-, 61-, and 190-fold of control RS, respectively, with 1 uM ETP-46464, 50 nM UCN-01, or combined treatment).

Dorsomorphin dihydrochloride is a potent and selective AMPK inhibitor, that is competitive with ATP, with Ki of 109±16 nM in the absence of AMP.Rigosertib (sodium) is a non-ATP-competitive inhibitor of PLK1 with IC50 of 9 nM, and shows 30-fold greater selectivity against PLK2.

XMD8-92 is a highly selective ERK5/BMK1 inhibitor with dissociation constant (Kd) value of 80 nM.Danusertib is a pyrrolo-pyrazole and aurora kinase inhibitor with IC50 of 13, 79, and 61 nM for Aurora A, B, and C, respectively.Vandetanib is a potent inhibitor of VEGFR2 with IC50 of 40 nM.

DMAT is a potent and specific CK2 inhibitor with an IC50 value of 130 nM.

CI-1040 (PD184352) is an orally active, highly specific, small-molecule inhibitor of MEK with an IC50 of 17 nM for MEK1.

CCT241533 hydrochloride is a potent and selective ATP competitive inhibitor of CHK2 with an IC50 of 3 nM and Ki of 1.16 nM.

Salubrinal is an inhibitor of phosphatases (PP1) that act on the eukaryotic translation initiation factor 2 subunit (eIF2α), with IC50 of 1.7 µM for blocking PP1 activity.NVS-PAK1-1 is a potent and selective allosteric PAK1 inhibitor with an IC50 of 5 nM.

MK 2206 is an orally active allosteric Akt inhibitor with IC50 of 5 nM/12 nM/65 nM for Akt1/2/3, respectively.

PD0325901 is a selective and non ATP-competitive MEK inhibitor with IC50 of 0.33 nM, roughly 500-fold more potent than CI-1040 on phosphorylation of ERK1 and ERK2.Dovitinib(CHIR-258; TKI258) lactate is a potent inhibitor of fibroblast growth factor receptor 3 (FGFR3) with an IC50 of 5 nM.

Regorafenib is a multi-target inhibitor for VEGFR1/2/3, PDGFRβ, Kit, RET and Raf-1 with IC50s of 13/4.2/46, 22, 7, 1.5 and 2.5 nM, respectively.

Olmutinib (HM61713; BI-1482694) is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor with IC50 values of 9.2 nM and 10 nM in HCC827 and H1975 cell, respectively. Crizotinib hydrochloride is a potent inhibitor of c-Met and ALK with IC50 of 11 nM and 24 nM in cell-based assays, respectively.

Vemurafenib is a novel and potent inhibitor of B-RAF kinase, with IC50 values of RAFV600E (31 nM) and c-RAF-1 (48 nM).PF-3758309 is an inhbitor of PAK with IC50 of 1.3 nM for PAK4.

MRT68921 hydrochloride is the most potent inhibitor of both ULK1 and ULK2, with greater than a 15-fold reduction in the IC50 for ULK1 (2.9 nM) and greater than a 30-fold reduction for ULK2 (1.1 nM). IC50 value: 2.9/1.1 nM (ULK1/2)Target: ULKin vitro: MRT68921 potently inhibits ULK1 and ULK2 and block autophagy in cells. MRT68921 specifically blocks autophagic flux through ULK1 inhibition. MRT68921 is able to inhibit the WT-restored ATG13 phosphorylation and autophagy similarly to cells expressing endogenous ULK1. [1]BX-912 is a selective inhibitor of 3-Phosphoinositide-dependent Kinase-1 (PDK1) with IC50 of 12 nM; >10 fold selectivity over PKA, PKC, C-Kit, EGFR etc.IC50 value: 12 nM [1]Target: PDK1

Ro 5126766 (CH5126766) is a potent and selective dual RAF/MEK inhibitor. For SK-MEL-28, SK-MEL-2, MIAPaCa-2, and SW480 cell lines, the IC50 is determined by WST-8 assay is 65, 28, 40, and 46 nM, respectively.IC50 value: 65 nM (SK-MEL-28), 28 nM(SK-MEL-2), 40 nM (MIAPaCa-2), and 46 nM (SW480)Target: RAF/MEKin vitro: Ro 5126766 induced G1 cell cycle arrest in two melanoma cell lines with the BRAF V600E or NRAS mutation. In these cells, the G1 cell cycle arrest was accompanied by up-regulation of the cyclin-dependent kinase inhibitor p27 and down-regulation of cyclinD1. Ro 5126766 was more effective at reducing colony formation than a MEK inhibitor in NRAS- or KRAS-mutated cells. In the RAS-mutated cells, Ro 5126766 suppressed the MEK reactivation caused by a MEK inhibitor. [1]in vivo: Ro 5126766 suppressed the tumor growth without body weight loss more than 10% in mice. In addition, Ro 5126766 suppressed the tumor growth in SK-MEL-2 xenograft model.[1]

Sapitinib(AZD8931) is a reversible, ATP competitive inhibitor of EGFR, ErbB2 and ErbB3 with IC50 of 4 nM, 3 nM and 4 nM respectively.IC50 value: 4/3/4 nM(EGFR/ERBB2/ERBB3) [1]Target: EGFR inhibitorin vitro: ZD8931 shows different potency to NSCLC and SCCHN cell lines. AZD8931 has high sensitivity to PC-9 cells (EGFR activating mutation) with GI50 of 0.1 nM and low activity to NCI-1437 cells with GI50 above 10 μM. AZD8931 exhibits more potency against phospho-EGFR, phospho-erbB2 and phospho-erbB3 than either lapatinib or gefitinib in PE/CA-PJ41, PE/CA-PJ49, DOK and FaDu cells [1]. AZD8931 significantly suppressed cell growth of IBC cells and induced apoptosis of human IBC cells in vitro [2].in vivo: AZD8931 reveals antitumor activity in BT474c, Calu-3, LoVo, FaDu and PC-9 xenografts. AZD8931 could reduce p-Akt, Ki67 expression and p-ERK in BT474c xenografts following acute treatment. AZD8931 also causes induction of the M30 apoptosis marker. Furthermore, AZD8931 shows greater proapoptotic effect compared with gefitinib and lapatinib in LoVo xenografts [1]. AZD8931 monotherapy inhibited xenograft growth and the combination of paclitaxel + AZD8931 was demonstrably more effective than paclitaxel or AZD8931 alone treatment at delaying tumor growth in vivo in orthotopic IBC models [2]. AZD8931 exhibited good pharmacokinetics in preclinical species and showed superior activity in the LoVo tumor growth efficacy model compared to close analogues [3].

Pazopanib Hcl (GW-786034) is a novel multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFR, FGFR, c-Kit and c-Fms with IC50 of 10 nM, 30 nM, 47 nM, 84 nM, 74 nM, 140 nM and 146 nM, respectively.IC50 value: 10/30/47/84/74/140/146 nM (pan VEGFR1/2/3/PDGFR/FGFR/c-Kit/c-Fms) [1]Target: VEGFR/PDGFR/VEGFR/CSF1Rin vitro: Pazopanib potently inhibits VEGF-induced phosphorylation of VEGFR2 in HUVEC cells with IC50 of 8 nM [1]. PPazopanib shows dose-dependent growth inhibition in all synovial sarcoma cell lines including SYO-1 and HS-SY-II cells. Proliferation of SYO-1 and HS-SY-II cells is inhibited even at 1 μg/mL of Pazopanib and is completely abolished at 5 μg/mL. Pazopanib induces G1 arrest, and thereby suppresses the growth of synovial sarcoma cells. Phosphorylation of Akts, GSK-3β, JNKs, p70 S6 Kinase, and mTOR is suppressed in Pazopanib-treated SYO-1 cells compared with that in the vehicle-treated cells [2]. Pazopanib between 20 m g/mL and 22.5 m g/mL shows an increasing reduction of RPE cell viability [3]. in vivo: The mice treated with 30 mg/kg or 100 mg/kg Pazopanib reveals a significant decrease in tumor burden compared with the mice treated with vehicle or 10 mg/kg Pazopanib. Treatment with Pazopanib is well-tolerated and there is no significant difference in the body weight among the mice in each group [2].

PF-03814735 is a novel, potent, orally bioavailable, reversible small-molecule Aurora kinase inhibitor with IC50 of 0.8, 5, 10 and 22 nM for Aurora A, Aurora B, Flt 1 and FAk, respectively. IC50 Value: 0.8 nM(Aurora A); 5 nM(Aurora B); 10 nM(Flt1); 22 nM(FAK); 30 nM(TrkA)Target: Aurora A/BPF-03814735 possesses potential antineoplastic activity. Aurora kinase inhibitor PF-03814735 binds to and blocks Aurora kinases A and B, which may result in the prevention of cellular division and proliferation in tumor cells that overexpress these kinases. In intact cells, the preventive activity of PF-03814735 on the Aurora1 and Aurora2 kinases attenuates levels of phospho-Aurora1, phosphohistone H3, and phospho-Aurora2. PF-03814735 generates a block in cytokinesis, leading to prevention of cell proliferation and the formation of polyploid multinucleated cells. Although PF-03814735 generates significant prevention of several other protein kinases, the predominant biochemical effects in cellular assays are consistent with inhibition of Aurora kinases. Once-daily oral injection of PF-03814735 to mice bearing human xenograft tumors generates an attenuation in phosphohistone H3 in tumors at doses that are tolerable and that result in significant inhibition of tumor growth. The combination of PF-03814735 and docetaxel in xenograft mouse tumor models shows additive tumor growth inhibition.UNC2025 is a potent and orally bioavailable Mer/Flt3 dual inhibitor with IC50 of 0.8/0.74 nM for Mer/Flt3.IC50 value: 0.8/0.74 nM(MER/FLT3)Target: Mer/Flt3 inhibitorUNC2025 was capable of inhibiting Mer phosphorylation in vivo, following oral dosing as demonstrated by pharmaco-dynamic (PD) studies examining phospho-Mer in leukemic blasts from mouse bone marrow. Kinome pro ling versus more than 300 kinases in vitro and cellular selectivity assessments demonstrate that 11 has similar subnanomolar activity against Flt3, an additional important target in acute myelogenous leukemia (AML), with pharmacologically useful selectivity versus other kinases examined.

GW843682X is a selective PLK1 and PLK3 inhibitor with IC50s of 2.2 nM(PLK1) and 9.1 nM(PLK3); displays > 100-fold selectivity over ~30 other kinases tested including cdk1 and cdk2.IC50 Value: 2.2/9.1 nM(PLK1/3) [1]Target: PLKGW843682X is a selective inhibitor of polo-like kinase 1 (PLK1) and polo-like kinase 3 (PLK3) (IC50 values are 2.2 and 9.1 nM respectively). GW843682X displays > 100-fold selectivity over ~30 other kinases tested including cdk1 and cdk2. GW843682X inhibits proliferation of most tumor cells in vitro and is selective over normal diploid fibroblasts. GW843682X significantly inhibited cell growth in all 18 cell lines. Concentrations, which inhibited cell growth by 50% compared with untreated controls after 72 h, ranged from 0.02 to 11.7 μmol/l. Apart from the N-Myc-amplified neuroblastoma cell lines, the osteosarcoma cell lines MNNG-HOS and OST, which are highly resistant to standard anticancer drugs, were sensitive to GW843682X. The toxicity of GW843682X was dependent neither on the ATP binding cassette drug transporter expression nor on the p53 mutation status.

AZD7545 is a novel, selective small-molecule inhibitor of PDHK2 (PDH kinase2) with an IC50 of 36.8 nM and 6.4 nM for PDHK1 and PDHK2 respectively.IC50 Value: 36.8 nM (PDHK1); 6.4 nM (PDHK2) [1]Target: PDHK1/2in vitro: The IC50 values for inhibition of PDHK2 and PDHK1 by AZD7545 were 6.4 ± 2.2 nM (n = 6) and 36.8 ± 18 nM (n = 3) respectively. Other compounds in this series inhibited both PDHK1 and PDHK2 and a consistent trend of reduced potency (5-15-fold) towards PDHK1, as compared with PDHK2, was observed. In contrast, AZD7545 and related compounds failed to inhibit PDHK4 and paradoxically, at higher concentrations (>10 nM), AZD7545 stimulated PDHK4 activity [1]. In the presence of PDHK2, AZD7545 increased PDH activity with an EC(50) value of 5.2 nM. In rat hepatocytes, the rate of pyruvate oxidation was stimulated 2-fold (EC(50) 105 nM) [2].in vivo: A single dose of AZD7545 to Wistar rats increased the proportion of liver PDH in its active, dephosphorylated form in a dose-related manner from 24.7 to 70.3% at 30 mg/kg; and in skeletal muscle from 21.1 to 53.3%. A single dose of 10 mg/kg also significantly elevated muscle PDH activity in obese Zucker (fa/fa) rats. Obese, insulin-resistant, Zucker rats show elevated postprandial glucose levels compared with their lean counterparts (8.7 versus 6.1 mM at 12 weeks old). AZD7545 (10 mg/kg) twice daily for 7 days markedly improved the 24-h glucose profile, by eliminating the postprandial elevation in blood glucose [2]. An interestingobservation is that administration of maximally effective doses of AZD7545 and related compounds to rats results in the near-complete activation of PDH activity in liver, where PDHK2 is the major isoenzyme, while only partial activation of PDH activity is achieved in skeletal muscle and heart, tissues which express high levels of PDHK4. For example, following administration of a maximally effective dose of compound K (30 mg/kg) the percentage of PDH present in the active (dephosphorylated) state in liver is elevated from 35.3 ± 4.0% to 90.2 ± 2.2% while in skeletal muscle and heart PDH activity plateaus at 64.3 ± 2.3% and 61.8 ± 4.3% respectively. Further evidence for a link between in vitro isoenzyme selectivity and in vivo activity comes from the observation that in fasted rats the ability of AZD7545 toelevate PDH activity in liver is intact, while the activation of skeletal muscle PDH activity in response to the compound is severely blunted [1].

B-Raf inhibitor 1 is a potent and selective B-Raf inhibitor with cell IC50s of 0.31 uM and 2 nM for A375 proliferation and A375 p-ERK respectively.IC50 value: 0.31 uM and 2 nM for A375 proliferation and A375 p-ERK [1]Target: B-RafB-Raf inhibitor 1(Compound 13) binds to and stabilizes B-Raf in a DFG-out, inactive conformation in which the ATP pocket is partially filled by Phe595 and Gly596 from the DFG motif. Compound 13 exhibit low micromolar inhibition against wild type B-Raf cell lines, which may be due to off-target kinase activities oralternatively to pan-Raf inhibition, including Raf dimers. Compound 13 induced proliferation and hyperplasia in normal tissues of mice [1].SBE13 Hcl is a potent and selective PLK1 with IC50 of 0.2 nM; no inhibition om Aurora A kinase, Plk2 and Plk3.IC50 value: 0.2 nM [1]Target: PLK1 inhibitorin vitro: To test the selectivity of SBE13 for Plk1 we probed its inhibitory effect on aurora A kinase, Plk2, and Plk3. No decrease in aurora A kinase activity was observed, and only marginally decreased Plk2 (IC50>66μm) or Plk3 (IC50=875 nm) kinase activity was detected after 13 h release in the presence of SBE13 (p>0.05) [1]. Plk1 inhibition using SBE13 enhances the effects of Enzastaurin in cancer cells. HCT116(p53wt) and HCT116(p53-/-) cells confirmed the p53-dependence of different effects after Plk1 and PKCβ inhibition observed in HeLa and MCF-7 cells. Obviously, p53 protects cells from the cytotoxicity of Enzastaurin in combination with SBE13 [2].

BMS-536924 is an ATP-competitive IGF-1R/IR inhibitor with IC50 of 100 nM/73 nM.IC50 value: 100 nM (IGF-1R); 73 nM (IR) [1]Target: IGF-1R; IRin vitro: BMS-536924 also inhibits FAK and Lck with IC50 of 150 nM and 341 nM, respectively. BMS-536924 inhibits cellular proliferation and disrupts Akt and MAPK phosphorylation [1]. BMS-536924 inhibits IGF-I-stimulated IGF-1R signaling in MCF10A cells and blocks constitutive IGF-1R activity in CD8-IGF-1R-MCF10A. Preincubation of MCF10A cells with 1 μM BMS-536924 completely blocks the ability of IGF-I to stimulate IGF-1R phosphorylation. IGF-I stimulation results in increased phosphorylation of ERK1/2, GSK3β, and Akt. BMS-536924 inhibits this ligand-induced phosphorylation. Treatment of the CD8-IGF-1R-MCF10A cells with BMS-536924 results in a dose-dependent inhibition of phosphorylation with partial inhibition at 0.01 μM and 0.1 μM, but complete receptor inhibition at a concentration of 1 μM. Maximal inhibition of phosphorylated IGF-1R is observed as early as 10 minutes following incubation. BMS-536924 retains its ability to inhibit IGF-1R phosphorylation for up to 48 hours. Addition of BMS-536924 time-dependently inhibits Akt phosphorylation starting at 1 hour. By 48 hours, Akt activation is completely blocked [2]. in vivo: Oral administration of BMS-536924 at 100-300 mpk strongly inhibits IGR-1R Sal tumor model. Efficacy is also observed in the nonengineered Colo205 human colon carcinoma mode. Oral administration of 3 on a once a day schedule (100-300 mpk) or a twice a day schedule (50, 100 mpk) demonstrates antitumor activity in this tumor model. Oral glucose tolerance test (OGTT) shows 100 mpk (b.i.d.) causes a significant elevation in glucose levels after glucose challenge. The pharmacokinetic parameters of BMS-536924, administered orally in poly(ethylene glycol) 400 and water (80:20 v/v), are determined in mouse, rat, dog, and monkey. Good bioavailability is evident in all species. Significant nonlinear pharmacokinetics is observed in rodents at increasing p.o. dose [1]. Oral administration of 70 mg/kg BMS-536924 significantly inhibits tumor growth (TGBC-1TKB cells) inoculated in nude mice. BMS-536924 up regulates apoptosis in xenografts tumors. The treatment doesn't have adverse effects on the body weight of mice or the glucose levels at the time of death, suggesting tolerable toxicity [3].

Irbinitinib (ARRY-380; ONT-380) is a potent and selective HER2 inhibitor with an IC50 of 8 nM.

CH5424802 is a potent, selective, and orally available ALK inhibitor with IC50 of 1.9 nM, the dissociation constant (KD) value for ALK in an ATP-competitive manner is 2.4 nM using a competition-binding assay.

IKK 16 is a selective IκB kinase (IKK) inhibitor for IKK-2, IKK complex and IKK-1 with IC50s of 40 nM, 70 nM and 200 nM, respectively. Palbociclib hydrochloride is a highly specific inhibitor of Cdk4 (IC50=11 nM) and Cdk6 (IC50=16 nM), having no activity against a panel of 36 additional protein kinases.

LY2409881 is a novel selective inhibitor of IKK2 with IC50 of 30 nM; IC50 for IKK1 and other common kinases is at least one log higher.IC50 value: 30 nM [1]Target: IKK2 inhibitorin vitro: LY2409881 inhibited constitutively activated NF-κB, and caused concentration- and time-dependent growth inhibition and apoptosis in lymphoma cells. Pretreatment of LY10 with 10 umol/L of LY2409881 prevented the formation of phosphorylated IkB in samples treated with TNFa for 2, 20, and 60 minutes in the presence of abundant IkB protein [1]. in vivo: LY2409881 was safe to mice at three dose levels, 50, 100, and 200 mg/kg, all of which caused significant inhibition of tumor growth. LY2409881 suppressed the activity of the NF-κB subunit p65 in lymphoma cells treated by the HDAC inhibitor romidepsin, underlying a potential mechanism of the marked synergy observed of these two drugs [1].

AZ-5104 is a potent EGFR inhibitor, displays potent antitumor activities both in vitro and in vivo.Target: EGFRAZ-5104 is an active, demethylated metabolite of AZD-9291. AZ-5104 displays similar overall activity profile with AZD-9291, but is more potent against mutant EGFR forms, while hitting the wild-type EGFR form at a lower concentration thus demonstrating a smaller selectivity margin compared with the parent.Afatinib is an irreversible, dual EGFR/HER2 inhibitor, shows potent activity against wild-type and mutant forms of EGFR and HER2, with IC50 of 0.5 nM, 0.4 nM, 10 nM and 14 nM for EGFRwt, EGFRL858R, EGFRL858R/T790M and HER2, respectively.

CHIR-98014 is a selective GSK3 inhibitor with IC50s of 0.65 nM and 0.58 nM for GSK-3α and GSK-3β; potentiate insulin activation of glucose transport and utilization in vitro and in vivo.IC50 value: 0.65 nM/0.58 nM (GSK-3α/GSK-3β) [1]Target: GSK-3α/GSK-3βExposure of insulin receptor–expressing CHO-IR cells or primary rat hepatocytes to increasing concentrations of inhibitor CHIR 98014 resulted in a two- to threefold stimulation of the GS activity ratioabove basal. The concentrations of CHIR 98014 causing half-maximal GS stimulation (EC50) were 106 nmol/l for CHO-IR cells and 107 nmol/l for rat hepatocytes. CHIR 98014 activated the GS activity ratio in isolated type 1 skeletal muscle from insulin-sensitive lean Zucker and from insulin-resistant ZDF rats. Markedly diabetic and insulin-resistant db/db mice treated with 30 mg/kg CHIR 98014 also exhibited a significant reduction in fasting hyperglycemia within 4 h of treatment and showed improved glucose disposal during an ipGTT [1]. CHIR-99021 and SB-216763 had the lowest toxicities in mouse embryonic stem cells and CHIR-98014 and BIO the highest toxicities. Only CHIR-99021 and CHIR-98014 lead to a strong induction of the Wnt/beta-catenin pathway [2].Dasatinib is a potent and dual AblWT/Src inhibitor IC50 of 0.6 nM/0.8 nM respectively; also inhibits c-KitWT/c-KitD816V with IC50 of 79 nM/37 nM.

Bucladesine calcium salt(DC2797 calcium salt) is a membrane permeable selective activator of PKA.Target: PKABucladesine (bilateral infusion of 10 mM or 100 mM) leads to a significant reduction in escape latency and travel distance (showing an improvement in spatial memory) compared to the control, as assesed by Morris water maze task in male rats. Bucladesine at 1 mM and 5 mM concentrations infused within minutes after 0.5 mg nicotine infusion improves spatial memory retention in male rats [1]. Bucladesine (10 mM/side) combined with Nicotine (0.5 mM/side) results in a significant increase in the ChAT and VAChT immunoreactivity in CA1 regions, and increase in the optical density and amount of ChAT and VAChT immunostaining correlates with the decrease in escape latency and traveled distance in rats treated with Nicotine and low dose of Bucladesine [2]. Bucladesine is absorbed very rapidly and almost completely when the aqueous solution is applied to the site where the skin has been excised. Bucladesine is absorbed rapidly but slower than in the full-thickness abrasion rat model in the case of stripped skin [3]. Bucladesine (single or multiple administration of an emulsion containing 1.5%) is capable of significantly reducing the inflammatory oedema in the arachidonic acid induced ear oedema model in mice [4].

PIK-75 is a p110α inhibitor with IC50 of 5.8 nM (200-fold more potently than p110β), isoform-specific mutants at Ser773, and also potently inhibits DNA-PK with IC50 of 2 nM.IC50 value: 5.8/2 nM(p110α/DNA-PK) [1] [2]Target: p110α; DNA-PKin vitro: PIK-75 shows the impressive potency and isoform selectivity at p110α while the corresponding IC50 values are 1300 nM, 76 nM and 510 nM for other PI3K isoforms, p110β, -γ, and -δ, respectively. Furthermore, when binding to purified p110α, PIK-75 is a noncompetitive inhibitor with respect to ATP with Ki of 36 nM and competitive with respect to the substrate PI with Ki of 2.3 nM [1]. PIK-75 also shows potent inhibition of DNA-PK [2]. PIK-75 (1 μM) reduces cell survival by significantly decreasing mitochondrial activity in unstimulated nonasthmatic airway smooth muscle (ASM) cells, asthmatic ASM cells, and lung fibroblasts. While in TGFβ-stimulated ASM cells, PIK75 only decreases mitochondrial activity in asthmatic cells without effects in nonasthmatic cells [3].in vivo: In the ErbB3WT tumor model, PIK-75 reduces in vitro chemotactic response to HRGβ1 and lowers pAkt levels by 40%. Besides, PIK-75 significantly reduces tumor cell motility and in vivo invasion in ErbB3WT primary tumors [4]. In the CD1 male mice, PIK-75 leads to serious impairments in the insulin tolerance test (ITT) and glucose tolerance test (GTT), and an increase in glucose production during a pyruvate tolerance test (PTT) [5].

DCC-2618 is a potent inhibitor of c-Kit and c-Met with IC50s of <200 nM.PIK-294 is a highly selective p110δ inhibitor with IC50 of 10 nM, less potent to PI3Kα/β/γ.IC50 value: 10 nM(p110δ) [1]Target: p110δ inhibitorPIK-294 shows distinct patterns of isoform selectivity to inhibit different subsets of class I PI3K isoforms (p110β, p110δ, and p110γ) and exhibits low sensitivity to p110α with IC50 of 10 μM). The m-phenol moiety of PIK-294 is able to penetrate the deep-affinity pocket of the ATP binding site, and thus increases in vitro inhibitory activity.

PF-573228 is a potent and selective FAK inhibitor with IC50 of 4 nM for purified recombinant catalytic fragment of FAK.

WZ4003 is the first potent and highly specific NUAK kinase inhibitor with IC50 of 20 nM/100 nM for NUAK1/NUAK2, without significant inhibition on other 139 kinases.

Masitinib is a novel inhibitor for Kit and PDGFRα/β with IC50 of 200 nM and 540 nM/800 nM, and has weak inhibition to ABL and c-Fms.

CDK9-IN-1 is a novel, selective CDK9 inhibitor for the treatment of HIV infection.

VX-11e is a potent, selective, and orally bioavailable inhibitor of ERK with Ki < 2 nM.MK-1775 is a potent Wee1 inhibitor with IC50 of 5.2 nM.

GSK2126458 is a highly selective and potent inhibitor of PI3K with Ki of 0.019 nM/0.13 nM/0.024 nM/0.06 nM and 0.18 nM/0.3 nM for p110α/β/δ/γ, mTORC1/2, respectively.MLN 2480 is an orally active and selective inhibitor of pan-Raf kinase.

JNK-IN-8 is a potent JNK inhibitor with IC50 of 4.7 nM, 18.7 nM, and 1 nM for JNK1, JNK2, and JNK3, respectively.

LY2090314 is a potent inhibitor of glycogen synthase kinase-3 (GSK-3) with IC50 values of 1.5 nM and 0.9 nM for GSK-3α and GSK-3β, respectively.

FRAX486 is a p21-activated kinase (PAK) inhibitor with IC50s between 10-100 nM for PAK1-3.

GDC-0941 is a potent inhibitor of PI3Kα/δ with IC50 of 3 nM, with modest selectivity against p110β (11-fold) and p110γ (25-fold).

Poziotinib(NOV120101; HM781-36B) is an irreversible Pan-HER inhibitor with IC50s of 3/5/23 nM for HER1/HER2/HER4 respectively.IC50 value: 3/5/23 nM(HER1/HER2/HER4) [1]Target: pan-HER inhibitorin vitro: The IC50 levels of HM781-36B for N87 and SNU216 were 0.001 and 0.004 μmol/L, respectively, which was 10–1000 fold lower than the IC50 levels of other HER family TKIs. HM781-36B more potently inhibited the phosphorylation of HER family and downstream proteins, and induced apoptosis and G1 arrest compared to gefitinib or lapatinib [1]. HM781-36B is a potent inhibitor of EGFR in vitro, including the EGFR-acquired resistance mutation (T790M), as well as HER-2 and HER-4, compared with other EGFR tyrosine kinases inhibitors (erlotinib, lapatinib and BIBW2992). HM781-36B treatment of EGFR DelE746_A750-harboring erlotinib-sensitive HCC827 and EGFR L858R/T790M-harboring erlotinib-resistant NCI-H1975 NSCLC cells results in the inhibition of EGFR phosphorylation and the subsequent deactivation of downstream signaling proteins [2]. The addition of HM781-36B induced potent growth inhibition in both DiFi cells with EGFR overexpression and SNU-175 cells (IC50 = 0.003 and 0.005 μM, respectively). Furthermore, HM781-36B induced G1 arrest of the cell cycle and apoptosis, and reduced the levels of HER family and downstream signaling molecules, pERK and pAKT, as well as nonreceptor/cytoplasmic tyrosine kinase, BMX [3].in vivo: The growth of tumors in mice treated with HM781-36B alone or in combination with 5-FU was significantly inhibited compared with control mice, and tumor volume in mice receiving coadministraion of HM781-36B and 5-FU was smaller than tumor volume in mice receiving HM781-36B only [1].

Bucladesine is a membrane permeable selective activator of PKA.Target: PKABucladesine (bilateral infusion of 10 mM or 100 mM) leads to a significant reduction in escape latency and travel distance (showing an improvement in spatial memory) compared to the control, as assesed by Morris water maze task in male rats. Bucladesine at 1 mM and 5 mM concentrations infused within minutes after 0.5 mg nicotine infusion improves spatial memory retention in male rats [1]. Bucladesine (10 mM/side) combined with Nicotine (0.5 mM/side) results in a significant increase in the ChAT and VAChT immunoreactivity in CA1 regions, and increase in the optical density and amount of ChAT and VAChT immunostaining correlates with the decrease in escape latency and traveled distance in rats treated with Nicotine and low dose of Bucladesine [2]. Bucladesine is absorbed very rapidly and almost completely when the aqueous solution is applied to the site where the skin has been excised. Bucladesine is absorbed rapidly but slower than in the full-thickness abrasion rat model in the case of stripped skin [3]. Bucladesine (single or multiple administration of an emulsion containing 1.5%) is capable of significantly reducing the inflammatory oedema in the arachidonic acid induced ear oedema model in mice [4].

EMD 1214063 is a potent and selective c-Met inhibitor with IC50 of 4 nM, >200-fold selective for c-Met than IRAK4, TrkA, Axl, IRAK1, and Mer. IC50 Value: 4 nM [1]Target: c-Metin vitro: EMD 1214063 inhibits HGF-induced c-Met phosphorylation in A549 cells with IC50 of 6 nM. Treatment with EMD 1214063 induces a marked reduction of c-Met–constitutive phosphorylation in EBC-1 cells with IC50 of 9 nM. EMD 1214063 effectively blocka phosphorylation of the major downstream effectors of the c-Met enzyme, such as Grb2, Gab1, Sos, PLCγ, and phosphoinositide 3-kinase, in EBC-1, MKN-45, and Hs746T cells in the range of 1 to 10 nM. EMD 1214063 considerably inhibits the viability of MKN-45 cells with IC50 of less than 1 nM. Treatment with EMD 1214063 (as low as 0.1 nM) inhibits HGF-induced NCI-H441 cell migration, whereas concentrations of 100 nM to 1 μM almost completely prevents it.in vivo: EMD 1214063 treatment, at doses of 10 mg/kg or more, results in more than 90% inhibition of c-Met phosphorylation in Hs746T xenograft tumor for a period of at least 72 hours. EMD 1214063 induces more than 50% reduction of cyclin D1 expression, which persists after 96 hours upon treatment with doses of 100 mg/kg. A transient induction of p27 and cleaved caspase-3 are also observed upon treatment with EMD 1214063. EMD 1214063 (15 mg/kg, daily) treatment induces complete regression of gastric carcinoma xenografts Hs746T, in which c-Met is amplified, overexpressed, and activated in a ligand-independent fashion.

Apatinib is a selective VEGFR2 inhibitor with IC50 of 1 nM. Apatinib also potently suppresses the activities of Ret, c-Kit and c-Src with IC50s of 13, 429 and 530 nM, respectively. Apatinib has no significant effects on EGFR, Her-2 or FGFR1 in concentrations up to 10 μM.

Imatinib is a known inhibitor of the c-Kit, Bcr-Abl, and PDGFR tyrosine kinases, inhibits the SLF-dependent activation of c-Kitwt kinase with IC50 of ~100 nM, which is similar to the concentration requires for inhibition of Bcr-Abl and PDGFR.Toceranib phosphate (SU 11654; PHA 291639) is a kinase inhibitor with both antitumor and antiangiogenic activity through inhibition of KIT, vascular endothelial growth factor receptor 2, and PDGFRβ.IC50 value:Target: Kit; PDGFRβ; VEGFR2

WZ4002 is a novel, mutant-selective EGFR inhibitor for EGFR(L858R)/(T790M) with IC50 of 2 nM/8 nM; does not inhibit ERBB2 phosphorylation (T798I).IC50 value: 2 nM/8 nM(EGFR L858R/T790M) [1]Target: Mutant EGFRin vitro: WZ4002 inhibits other EGFR genotypes E746_A750 and E746_A750/T790M with IC50 of 2 and 6 nM. Besides, WZ4002 suppresses widetype ERBB2 with an IC50 of 32 nM. WZ4002 inhibits EGFR, AKT and ERK1/2 phosphorylation in NSCLC cell lines and WZ4002 prevents of EGFR phosphorylation in NIH-3T3 cells expressing different EGFR T790M mutant alleles. For WZ4002, kinases that exhibited greater than 95% inhibition relative to the DMSO control at 10 μM are selected for measurement of their dissociation constants. WZ4002, which possesses an ortho-methoxy group at the C2-aniline substituent, is more selective for EGFR compared to WZ3146. WZ4002 is 100-fold less effective at inhibiting phosphorylation of WT EGFR compared to the quinazoline inhibitors. Similarly, WZ4002 prevents EGFR kinase activity of recombinant L858R/T790M protein more potently than of WT EGFR, while the opposite is observed with HKI-272 and gefitinib [1]. In addition, the phosphorylated EGFR of Src TKI-resistant H1975 cells, as well as HCC827 cells, is completely suppressed by the third generation EGFR TKI, WZ4002 [2].in vivo: In a 2-week efficacy study, WZ4002 treatment results in significant tumor regressions compared to vehicle alone in both T790M containing murine models [1]. Treatment with low-dose WZ4002, and high-dose WZ4002 leads to mean decreases in tracer uptake of 26%, and 36%, respectively [3].

AT7519 trifluoroacetate is a multi-CDK inhibitor for CDK1, 2, 4, 6 and 9 with IC50 of 10-210 nM; less potent to CDK3 and little active to CDK7. IC50 Value: 10-210 nMTarget: CDK1/2/4/6/9in vitro: AT7519 is an ATP competitive CDK inhibitor with a Ki value of 38 nM for CDK1. AT7519 is inactive against all non-CDK kinases with the exception of GSK3β (IC50 = 89 nM). AT7519 shows potent antiproliferative activity in a variety of human tumor cell lines with IC50 values ranging from 40 nM for MCF-7 to 940 nM for SW620 consistent with the inhibition of CDK1 and CDK2. AT7519 induces dose-dependent cytotoxicity in multiple myeloma (MM) cell lines with IC50 values ranging from 0.5 to 2 μM at 48 hours, with the most sensitive cell lines being MM.1S (0.5 μM) and U266 (0.5 μM) and the most resistant MM.1R (>2 μM). It does not induce cytotoxicity in peripheral blood mononuclear cells (PBMNC). AT7519 partially overcomes the proliferative advantage conferred by IL6 and IGF-1 as well as the protective effect of bone marrow stromal cells (BMSCs). AT7519 induces rapid dephosphorylation of RNA pol II CTD at serine 2 and serine 5 sites, and leads to the inhibition of transcription, partially contributing to AT7519 induced cytotoxicity of MM cells. AT7519 induces activation of GSK-3β by down-regulating GSK-3β phosphorylation, which also contributes to AT7519 induced apoptosis independent of the inhibition of transcription.in vivo: A twice daily dosing of AT7519 (9.1 mg/kg) causes tumor regression of both early-stage and advanced-stage s.c. tumors in the HCT116 and HT29 colon cancer xenograft models. AT7519 treatment (15 mg/kg) inhibits tumor growth and prolongs the median overall survival of mice in the human MM xenograft mouse model in association with increased caspase 3 activation.

CCT129202 is a Aurora kinase inhibitor with IC50 of 0.042 ± 0.022, 0.198 ± 0.05, and 0.227 ± 0.064 uM for Aurora A, Aurora B, and Aurora C, respectively.IC50 Value: 0.042 μM(Aurora A); 0.198 μM(Aurora B); 0.227 μM(Aurora C)Target: panAurora Kinasein vitro: CCT129202 is an ATP-competitive inhibitor of recombinant Aurora A kinase with a Ki of 49.8 nM. CCT129202 at 1 μM shows high selectivity for Aurora A and Aurora B with 92% and 60% inhibition, respectively. It inhibits FGFR3 slightly by 27%, and is not active against CRAF. CCT129202 inhibits proliferation in multiple cultures of human tumor cell lines with half-maximal growth inhibition (GI50) values ranging from 0.08 μM for MV4-11 to 1.7 μM for MDA-MB-157. The effects are in association with increased expression levels of Aurora A and Aurora B leading to aberrant mitosis. Treatment with CCT129202 (0.7 μM) causes the accumulation of HCT116 cells with ≥4N DNA content, leading to apoptosis in a time dependent manner. Application of CCT129202 in HCT116 cells causes decreased histone H3 phosphorylation and increased p53 protein stabilization, which are consistent with the inhibition of Aurora B and Aurora A, respectively. in vivo: Administration of CCT129202 at 100 mg/kg in athymic mice bearing s.c. HCT116 colon cancer xenografts causes ~50% reduction of histone H3 phosphorylation after 30 minutes of treatment, and significantly inhibits tumor growth by 57.7% compared to control mice after a period of 9 days of treatment.

GDC-0980 is a potent, class I PI3K inhibitor for PI3Kα/β/δ/γ with IC50 of 5 nM/27 nM/7 nM/14 nM in cell-free assays, respectively, and also a mTOR inhibitor with Ki of 17 nM in a cell-free assay, and highly selective versus other PIKK family kinases.

CNX-774 is a potent, selective, and orally available small molecule inhibitor of Btk (IC50< 1 nM) that forms a ligand-directed covalent bond with Cys-481, a non-conserved amino acid within the active site of the enzyme.IC50 Value: <1 nM [1]Target: Btk KinaseIn biochemical assays, CNX-774 has demonstrated potent inhibition of Btk with an IC50 of <1nM in a continuous-read assay. The covalent bonding of CNX-774 to Btk was confirmed by incubating recombinant Btk protein with a 10-fold molar excess of CNX-774 for 1 hour at room temperature and analysis by MALDI-TOF MS. A shift of protein mass corresponding to the molecular weight of CNX-774 confirmed the covalent bonding of CNX-774 to Btk. Digestion of the covalently bonded Btk with pepsin followed by MSMS analysis established the bonding of CNX-774 to Cys-481. Cellular potency as well as prolonged duration of action of CNX-774 was demonstrated in Ramos cells by using a biotinylated covalent probe that targets the same Cysteine residue as CNX-774.CNX-774 was found to be >90% extractable after 2 hrs of incubation in both rat and human whole blood. These results demonstrate that CNX-774 has potent inhibitory activity towards the intended target, Btk, while achieving remarkable specificity in a variety of assays designed to assess off-target reactivity towards abundant cellular thiols and blood proteins.AZD-9291 is a third generation irreversible EGFR tyrosine kinase inhibitor with selectivity against mutant versus wild-type forms of EGFR, shows an apparent IC50 of 12 nM against L858R and 1 nM against L858R/T790M in EGFR recombinant enzyme assay.

Regorafenib monohydrate is a multi-target inhibitor for VEGFR1/2/3, PDGFRβ, Kit, RET and Raf-1 with IC50s of 13/4.2/46, 22, 7, 1.5 and 2.5 nM, respectively.PND-1186 is a substituted pyridine reversible inhibitor of FAK activity with IC50 of 1.5 nM in vitro.Cabozantinib is a potent multiple RTKs inhibitor that inhibits VEGFR2, c-Met, Kit, Axl and Flt3 with IC50 of 0.035, 1.3, 4.6, 7 and 11.3 nM, respectively.

PHA-680632 is potent inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 27 nM, 135 nM and 120 nM, respectively. IC50 Value: 27 nM (Aurora A); 135 nM (Aurora B); 120 nM(Aurora C)Target: Aurora Kinasein vitro: PHA-680632 potently inhibits all three Aurora kinases (A, B, and C) with IC50 values of 27, 135, and 120 nM, respectively. PHA-680632 is selective for Aurora kinases, with 10- to 200-fold higher IC50 for FGFR1, FLT3, LCK, PLK1, STLK2, VEGFR2, and VEGFR3, and with IC50 higher than 10 μM for another 22 kinases. PHA-680632 shows potent anti-proliferative effects in a wide range of cell types with IC50 values of 0.06–7.15 μM, including HeLa, HCT116, HT29, LOVO, DU145, and NHDF cells. PHA-680632 (0.5 μM) causes polyploidy in tumor cells. The mechanism of action of PHA-680632 is in agreement with inhibition of Aurora kinases. PHA680632 in association with radiation leads to additive effects in cancer cells, especially in the p53-deficient cells. Combined ionising radiation (IR) and treatment of PHA680632 (100–400 nM) prior to IR leads to an enhancement of radiation-induced Annexin V positive cells, micronuclei formation, and Brca1 foci formation only in HCT116 cells with deficient p53, other than the p53 wild-type counterparts. in vivo: HA-680632 (15–60 mg/kg) inhibits tumor growth in mice xenografts models of HL60, A2780, and HCT116 cells, by reducing tumor cell proliferation and increasing apoptosis. PHA-680632 (45 mg/kg) suppresses growth of activated ras-driven mammary tumors in mouse mammary tumor virus v-Ha-ras transgenic mice and results in complete tumor stabilization and partial regression.

NVP-BHG712 is a specific EphB4 inhibitor with ED50 of 25 nM that discriminates between VEGFR and EphB4 inhibition; also shows activity against c-Raf, c-Src and c-Abl with IC50 of 0.395 μM, 1.266 μM and 1.667 μM, respectively.IC50 value: 25 nM(EC50)Target: EphB4 receptor;c-Raf; c-Srcin vitro: NVP-BHG712 treatment also dose dependently leads to the inhibition of RTK autophosphorylation in stable transfected A375 melanoma cells with EC50 of 25 nM and 4.2 μM for EphB4 and VEGFR2, respectively [1].in vivo: In a growth factor-induced angiogenesis model, NVP-BHG712 (3 mg/kg, p.o) significantly suppresses VEGF stimulated tissue formation and vascularization by inhibiting EphB4 forward signaling. Furthermore, NVP-BHG712 (10 mg/kg/kg, p.o.) potently reverses VEGF enhanced tissue formation and vessel growth. NVP-BHG712 (3 mg/kg, p.o.) shows a long lasting exposure with concentrations around 10 μM in plasma as well as in lung and liver tissue for up to 8 hours, and thus results in a long lasting inhibition of EphB4 kinase activity in mice [1].

AMG 900 is a potent and highly selective pan-Aurora kinases inhibitor with IC50 of 5 nM, 4 nM and 1 nM for Aurora A, B and C, respectively.

TAK-733 is a potent and selective MEK allosteric site inhibitor for MEK1 with IC50 of 3.2 nM, inactive to Abl1, AKT3, c-RAF, CamK1, CDK2, c-Met, etc.IC50 Value: 3.2 nM [1]Target: MEK1in vitro: Sensitivity of cutaneous and uveal melanoma cell lines to TAK733 was investigated. five cutaneous melanoma cell lines wild type for mutations in NRAS, BRAF, GNAQand GNA11 and only one was highly sensitive to TAK733 with IC50s below 1 nM, while two were considered sensitive with IC50 less than 10 nM. All five uveal melanoma cell lines were sensitive to TAK733 with IC50 values below 10 nM, with three of them being highly sensitive. All these cell lines carried GNAQ or GNA11 driver mutations. Inhibition of oncogenic MAPK signaling through MEK1 and MEK2 by TAK733 results in antitumor activity in vitro against a large subset of melanoma cell lines[1].in vivo: The in vivo antitumor activity of TAK-733, an investigational potent, selective, non-ATP-competitive allosteric inhibitor of MEK, in combination with alisertib, an investigational potent, selective, reversible, ATP-competitive inhibitor of Aurora A kinase, was examined in experimental human solid tumor xenograft models including NSCLC (NCI H23 [KRAS and LKB1 mutations]), CRC (SW620 [KRAS, APC, p53 mutations]), and pancreatic cancer (Panc 1 and Capan 1 [KRAS mutations] and BxPC-3 [No MAPK mutations]) models in immunocompromised mice[2]. Clinical trail: TAK733 clinical trail I is on the way for cancer(Melanoma, NSCLC, colorectal, breast cancer [3].

TAK-901 is a novel inhibitor of Aurora A/B with IC50 of 21 nM/15 nM. IC50 Value: 21 nM(Aurora A); 15 nM(Aurora B)Target: Aurora A/Bin vitro: TAK-901 inhibits Aurora A-TPX2 and Aurora B-INCENP in tight binding, time-dependent manner. Dissociation of TAK-901 from Aurora B-INCENP is slow with at 1/2 of 920 minutes, and the affinity constant for TAK-901 binding to Aurora B-INCENP is determined to be 0.02 nM. TAK-901 induces inhibition of cell proliferation in cultured human cancer cell lines from different tissues with IC50s ranging from 40 to 500nM. Consistent with Aurora B inhibition, TAK-901 treatment produces polyploidy in human PC3 prostate cancer and HL60 acute myeloid leukemia cells as measured by immunofluorescence and flow cytometry. Examination of a broad panel of kinases reveals that multiple kinases, including FLT3, FGFR and the Src family kinases, are inhibited by TAK-901 with IC50 values similar to those for Aurora A and B. In cells, TAK-901 suppresses the Flt3 and FGFR2 autophosphorylation with IC50 values close to that of Aurora B as measured by cellular histone H3 phosphorylation, whereas the IC50s for inhibition of cellular Src and Bcr Abl are 20-fold weaker. In a panel of pathway specific reporter-based cell models, TAK-901 inhibits the NFkB and JAK/STAT pathways with submicromolar potency.in vivo:PI-3065 is a potent inhibitor of PI3K p110δ, with IC50 and Ki values of 5 nM and 1.5 nM, and exhibits less potent activity against p110α, p110β, p110γ with IC50s of 910, 600, >10000 nM.AZD1152-HQPA is a highly selective Aurora B inhibitor with IC50 of 0.37 nM in a cell-free assay, and appr 3700 fold more selective for Aurora B over Aurora A.

GSK1070916 is a reversible and ATP-competitive inhibitor of Aurora B/C with IC50 of 3.5 nM/6.5 nM; displays >100-fold selectivity against the closely related Aurora A-TPX2 complex(IC50=490 nM).IC50 Value: 3.5 nM(Aurora B); 6.5 nM(Aurora C)Target: Aurora B/Cin vitro: GSK1070916 selectively inhibits Aurora B and Aurora C with Ki of 0.38 nM and 1.5 nM over Aurora A with Ki of 490 nM. Inhibition of Aurora B and Aurora C is time-dependent, with an enzyme-inhibitor dissociation half-life of >480 min and 270 min respectively. In addition, GSK1070916 is also a competitive inhibitor with respect to ATP. Human tumor cells treated with GSK1070916 shows dose-dependent inhibition of phosphorylation on serine 10 of Histone H3, a substrate specific for Aurora B. Moreover, GSK1070916 inhibits the proliferation of tumor cells with EC50 values of <10 nM in over 100 cell lines spanning a broad range of tumor types, with a median EC50 of 8 nM. Although GSK1070916 has potent activity against proliferating cells, a dramatic shift in potency is observed in primary, nondividing, normal human vein endothelial cells. Furthermore, GSK1070916-treated cells do not arrest in mitosis but instead fails to divide and become polyploid, ultimately leading to apoptosis. In another study, it is also reported high chromosome number associated with resistance to the inhibition of Aurora B and C suggests cells with a mechanism to bypass the high ploidy checkpoint are resistant to GSK1070916.in vivo: GSK1070916 (25, 50, or 100 mg/kg) shows dose-dependent inhibition of phosphorylation of an Aurora B–specific substrate in mice and consistent with its broad cellular activity, has antitumor effects in 10 human tumor xenograft models including breast, colon, lung, and two leukemia models.

BLU9931 is a potent, selective, and irreversible FGFR4 inhibitor with IC50 of 3 nM, about 297-, 184-, and 50-fold selectivity over FGFR1/2/3, respectively.TG101209 is a selective JAK2 inhibitor with IC50 of 6 nM, less potent to Flt3 and RET with IC50 of 25 nM and 17 nM, appr 30-fold selective for JAK2 than JAK3, and sensitive to JAK2V617F and MPLW515L/K mutations; TG101209 inhibit BRD4 activity with IC50 of 130 nM.

Defactinib is a novel FAK inhibitor, which inhibits FAK phosphorylation at the Tyr397 site in a time- and dose-dependent manner.

BMS 777607 is a Met-related inhibitor for c-Met, Axl, Ron and Tyro3 with IC50s of 3.9 nM, 1.1 nM, 1.8 nM and 4.3 nM, respectively, and 40-fold more selective for Met-related targets than Lck, VEGFR-2, and TrkA/B, with more than 500-fold greater selectivity versus all other receptor and non receptor kinases.

SCIO-469 is a selective ATP-competitive p38 inhibitor with IC50 of 9 nM for p38αin vitro, about 10-fold selectivity for p38α over p38β, and at least 2000-fold selectivity for p38α over an in vitro panel of 20 other kinases, including other MAK kinases. target: p38IC50: 9 nM; [1]In vitro: SCIO-469 decreased constitutive p38α MAPK phosphorylation of both 5T2MM and 5T33MM cells. SCIO-469 also inhibits secretion and expression of the osteoclast-activating factors IL-11, receptor activator of NF-κB ligand, and macrophage inflammatory protein 1α, and prevents human osteoclast activationIn. It can also inhibit multiple myeloma growth and prevents bone disease in the 5T2MM and 5T33MM models.In vivo: targeting p38α MAPK with SCIO-469 decreases myeloma burden in addition to preventing the development of myeloma bone disease. [2]

UNC2025 hydrochloride is a potent and orally bioavailable Mer/Flt3 dual inhibitor with IC50 of 0.8/0.74 nM for Mer/Flt3.IC50 value: 0.8/0.74 nM (MER/FLT3)Target: Mer/Flt3 inhibitorUNC2025 was capable of inhibiting Mer phosphorylation in vivo, following oral dosing as demonstrated by pharmaco-dynamic (PD) studies examining phospho-Mer in leukemic blasts from mouse bone marrow. Kinome profiling versus more than 300 kinases in vitro and cellular selectivity assessments demonstrate that 11 has similar subnanomolar activity against Flt3, an additional important target in acute myelogenous leukemia (AML), with pharmacologically useful selectivity versus other kinases examined.CCT196969, a pan-Raf inhibitor, inhibits B-Raf with an IC50 of 0.1 μM.

ZM 447439 is a selective and ATP-competitive inhibitor for Aurora A and Aurora B with IC50 of 110 nM, 130 nM respectively, > 8 fold selectivity than Aurora C, MEK1, Src.IC50 Value: 110 nM( for Aurora A); 130 nM (for Aurora B) [1]Target: Aurora Kinasein vitro: ZM-447439 time- and dose-dependently inhibits the growth of all three cell lines with IC50 values of 3 μM (BON), 0.9 μM (QGP-1) and 3 μM (MIP-101) after 72 hours of continuous exposure. In addition, ZM-447439 potently induces cell apoptosis by promoting DNA fragmentation and caspase 3 and 7 activation, and arrests GEP-NET cells in the G0 /G1and G2/M phase of the cell cycle. [2] In mouse embryo, inhibition of Aurora kinase activity by ZM-447439 results in abnormalities during mitosis by regulating the phosphorylation of histone H3 serine 10 (H3S10Ph) from G2 to metaphase with different perturbations in each embryonic cycle. [3] A recent study shows that ZM-447439 exhibits growth inhibitory and proapoptotic effect on cervical cancer SiHa cells, and enhances the chemosensitivity to cisplatin. in vivo:

Enzastaurin is a potent PKCβ selective inhibitor with IC50 of 6 nM, 6- to 20-fold selectivity against PKCα, PKCγ and PKCε.TP-0903 is a potent and selective Axl receptor tyrosine kinase inhibitor with an IC50 value of 27 nM.PDK1 inhibitor is a potent and selective inhibitor of PDK1 with potential as anticancer agent.

ALK inhibitor 2 is a novel and selective inhibitor for the ALK kinase.

Alisertib is a selective Aurora A inhibitor with IC50 of 1.2 nM, and is more selective for Aurora A than Aurora B.

Dabrafenib is an ATP-competitive inhibitor of BRAF with IC50s of 5 nM and 0.6 nM for CRAF and BRAFV600E, respectively.GW 5074 is a potent and selective c-Raf inhibitor with IC50 of 9 nM, and has no effect on the activities of JNK1/2/3, MEK1, MKK6/7, CDK1/2, c-Src, p38 MAP, VEGFR2 or c-Fms.

KX2-391 Mesylate is an inhibitor of Src that targets the peptide substrate site of Src, with GI50 of 9-60 nM in cancer cell lines.

IPI549 is a potent and selective PI3Kγ Inhibitor with IC50 of 16 nM.ALK-IN-1 is a potent and selective active inhibitor of anaplastic lymphoma kinase(ALK), Patent US20140066406 A1.

Cobimetinib is a novel selective MEK inhibitor, and the IC50 value against MEK1 is 4.2 nM. NMS-1286937 is a potent, selective and orally available PLK1 inhibitor, with IC50 of 2 nM.

GSK461364 is a potent Polo-like kinase 1 (PLK1) inhibitor with a Ki value of 2.2 nM.

KU-60019 is an improved ATM kinase-specific inhibitor with IC50 of 6.3 nM.

Hesperadin is a ATP-competitive inhibitor of Aurora B kinase with IC50 of 250 nM.IC50 Value: 250 nMTarget: Aurora Bin vitro: Hesperadin prevents the phosphorylation of recombinant trypanosome histone H3 by the T. brucei Aurora kinase-1 (TbAUK1) from pathogenic Trypanosoma brucei with IC50 of 40 nM in vitro kinase assays. Hesperadin significantly inhibits cell growth of cultured infectious bloodstream forms (BF) with IC50 of 48 nM, and only weakly inhibits cell growth of insect stage procyclic forms (PF) with IC50 of 550 nM. Hesperadin inhibits the ability of immunoprecipitated Aurora B to phosphorylate histone H3 with IC50 of 250 nM and markedly reduces the activity of other kinases (AMPK, Lck, MKK1, MAPKAP-K1, CHK1, and PHK) at a concentration of 1 μM. In contrast, only 20-100 nM of Hesperadin is sufficient to induce the loss of mitotic histone H3-Ser10 phosphorylation in HeLa cells. Hesperadin treatment causes defects in mitosis and cytokinesis, leading to stoppage of proliferation of HeLa cells and polyploidization, which can be specifically ascribed to the inhibition of Aurora B function during the process of chromosome attachment. Hesperadin (100 nM) quickly overrides the mitotic arrest induced by taxol or monastrol but not by nocodazole. Hesperadin and nocodazole treatment in HeLa cells abolishes kinetochore localization of BubR1 and diminishes the intensity of Bub1 at kinetochores, suggesting that Aurora B function is required for efficient kinetochore recruitment of BubR1 and Bub1, which in turn might be necessary for prolonged checkpoint signaling. in vivo:

CEP-32496 is a highly potent inhibitor of BRAF(V600E/WT) and c-Raf with Kd of 14 nM/36 nM and 39 nM, also potent to Abl-1, c-Kit, Ret, PDGFRβ and VEGFR2, respectively; insignificant affinity for MEK-1, MEK-2, ERK-1 and ERK-2. IC50 value: 14 nM/36 nM(Kd,BRAF(V600E/WT) ); 39 nM (Kd,C-Raf) Target: B-Raf/C-RafCEP-32496 is a potent BRAF inhibitor in an in vitro binding assay for mutated BRAF(V600E) (K(d) BRAF(V600E) = 14 nM) and in a mitogen-activated protein (MAP)/extracellular signal-regulated (ER) kinase (MEK) phosphorylation (pMEK) inhibition assay in human melanoma (A375) and colorectal cancer (Colo-205) cell lines (IC(50) = 78 and 60 nmol/L). In vitro, CEP-32496 has multikinase binding activity at other cancer targets of interest; however, it exhibits selective cellular cytotoxicity for BRAF(V600E) versus wild-type cells.

MGCD-265-analog (structurally related to MGCD-265) is an orally bioavailable multitargeted tyrosine kinase inhibitor with potential antineoplastic activity with IC50 of 29 nM and 10 nM for c-Met and VEGFR2, respectively.IC50 value:10 nM (VEGFR2), 29 nM(c-Met) [1]Target:VEGFR, c-Metin vivo: MGCD-265-analog has a reasonable half-life, 1.2 h in rats and 5.8 h in dogs, and has an acceptable clearance, 0.33 L/(kg h) in rats and 1.1 L/(kg h) in dogs. The steady state volume of distribution was low in rats (0.25 L/kg) and reasonable in dogs (1.5 L/kg), while the oral bio-availability was determined to be 12% and 42% in rats and dogs, respectively. GCD-265-analog performed well in vivo against a panel of different human tumor types, particularly those that are driven by or overexpress c-Met (MNNGHOS and MKN45). Tumor growth inhibition at a dose of 20 mg/kg po once daily ranged from 41% to 94%. MGCD-265-analog was found to show spill-over inhibition of a number of kinases in addition to the intended c-Met/VEGFR2 activity. MGCD-265-analog has significant antitumor activity in vivo.[1]

RAF265 (CHIR-265) is a potent selective inhibitor of C-Raf/B-Raf/B-Raf V600E with IC50 of 3-60 nM, and exhibits potent inhibition on VEGFR2 phosphorylation with EC50 of 30 nM.IC50 value: 3-60 nM (B-Raf); 30 nM(EC50 for VEGFR2) [1]Target: B-Raf; VEGFR2; B-Raf V600Ein vitro: RAF265 inhibits C-Raf, wild type B-Raf and mutant (V600E) B-Raf. RAF265 effectively block phosphorylation of Raf's downstream substrates MEK and ERK in cells and also kill melanoma and colorectal cancer cell lines harboring B-Raf mutations independent of PTEN mutation status. Raf kinase inhibition by RAF265 in mutant B-Raf melanoma cell lines causes cell cycle arrest and induces apoptosis, mimicking the effect of Raf RNAi in these cells. RAF265 also potently inhibits the phosphorylation of VEGFR2 and proliferation of VEGF-stimulated hMVEC [1]. In HT29 and MDAMB231 cells, RAF265 shows inhibitory activity with IC20 of 1 to 3 μM and IC50 of 5 to 10 μM, respectively. While RAF265 leads to a significant decrease in clonogenic survival in all tested cell lines, which means that RAF265 induces a dominant effect on clonogenic survival. Addition of RAF265 to RAD001 in HCT116 cells could lead to moderately decreased AKT, S6 protein, and 4EBP1 phosphorylation [2]. Raf265 markedly reduces the protein level of Bcl-2 and great inhibitory in CM- and NCI-H727 cells, while having no effect on the TRAIL susceptibility of BON1 and GOT1 cells [3]. in vivo: AF265 shows 71% to 72% TVI% (tumor volume inhibition percentage) in HCT116 xenografts at 12 mg/kg. While the combination of RAF265 and RAD001 shows enhanced antitumor activity with increased T10 (time to achieve a relative tumor volume of 10 times the initial tumor volume) and tumor growth delay. The combination of RAD001 and RAF265 also significantly enhances the activation of caspase-3 in HCT116 and MDAMB231 but not in A549 xenografts [2]. RAF265 inhibits FDG (2-deoxy-2-[18F]fluoro-d-glucose) accumulation and decreases the tumor volumes in A375M xenografts by orally dosed of 100 mg/kg [4].

CH5424802 Hydrochloride is a potent, selective, and orally available ALK inhibitor with IC50 of 1.9 nM, the dissociation constant (KD) value for ALK in an ATP-competitive manner is 2.4 nM using a competition-bind assay.

Regorafenib (BAY 73-4506) is a multi-target inhibitor for VEGFR1, VEGFR2, VEGFR3, PDGFRβ, Kit, RET and Raf-1 with IC50 of 13 nM/4.2 nM/46 nM, 22 nM, 7 nM, 1.5 nM and 2.5 nM, respectively. IC50 value: Target: VEGFR; Raf; PDGFRβin vitro: Regorafenib strongly prevents VEGFR2 autophosphorylation in NIH-3T3/VEGFR2 cells with IC50 of 3 nM. In HAoSMCs, regorafenib suppress PDGFR-β autophosphorylation after stimulation with PDGF-BB, with an IC50 of 90 nM. Regorafenib also inhibits FGFR signaling in MCF-7 breast cancer (BC) cells stimulated with FGF10. Regorafenib very potently inhibited the mutant receptors KITK642E and RETC634W, with IC50 of approximately 20 nM and 10 nM, respectively. Regorafenib inhibits the proliferation of VEGF165-stimulated HUVECs, with an IC50 of approximately 3 nM. Regorafenib prevents the proliferation of FGF2-stimulated HUVECs and of PDGF-BB-stimulated HAoSMCs with IC50 of 127 nM and 146 nM, respectively [1]. Regorafenib targets both tumor cell proliferation and tumor vasculature through inhibition of receptors of tyrosine kinases (VEGFR, KIT, RET, FGFR, and PDGFR) and serine/threonine kinases (Raf and p38MAPK) [2]. Regorafenib suppresses growth of human Hep3B, PLC/PRF/5 and HepG2 cells in a concentration- and time-dependent manner [3]. in vivo: Regorafenib reveals potent dose-dependent TGI in various preclinical human xenograft models in mice, with tumor shrinkages in breast MDA-MB-231 and renal 786-O carcinoma models. Regorafenib prevents not only the growth of syngeneic primary 4T1 breast tumors growing orthotopically in the fat pad, but also suppresses the formation of tumor metastasis in the lung [1].

H-89 (dihydrochloride) is a potent inhibitor of cyclic AMP-dependent protein kinase (protein kinase A) with IC50 of 48 nM and has weak inhibition on PKG, PKC, Casein Kinase, and others kinases.

BI 2536 is a potent and selective inhibitor of Plk1 with IC50 of 0.83 nM, and is also a potent inhibitor of BRD4 with IC50 of 25 nM. Tauroursodeoxycholate (TUDCA) inhibits neointimal hyperplasia by reducing proliferation and inducing apoptosis of smooth muscle cells by suppression of ERK via PKCα-mediated MKP-1 induction.Target: ERK [1]in vitro: Tauroursodeoxycholate (TUDCA) is a cytoprotective agent in a variety of cells including hepatocytes as well as an inducer of apoptosis in cancer cells. In this study, we investigated whether TUDCA could prevent neointimal hyperplasia by suppressing the growth and migration of VSMCs. TUDCA suppresses both viability and migration of VSMCs through inhibition of ERK phosphorylation, by induction of MKP-1 via PKCα. TUDCA suppresses the PDGF-mediated proliferation and migration of VSMCs. [1]in vivo: The membrane translocation of PKCα by TUDCA induced inhibition of cholangiocyte proliferation in bile duct-ligated rats. [1]PD173074 is a potent FGFR1 inhibitor with IC50 of 25 nM and also inhibits VEGFR2 with IC50 of 100-200 nM, 1000-fold selective for FGFR1 than PDGFR and c-Src.Dasatinib hydrochloride is a potent and dual AblWT/Src inhibitor IC50 of 0.6 nM/0.8 nM respectively; also inhibits c-KitWT/c-KitD816V with IC50 of 79 nM/37 nM.

ENMD-2076 tartrate has selective activity against Aurora A and Flt3 with IC50 of 14 nM and 1.86 nM, 25-fold selective for Aurora A than over Aurora B and less potent to VEGFR2/KDR and VEGFR3, FGFR1 and FGFR2 and PDGFRα.IC50 value: 14 nM (Aurora A); 1.86 nM (Flt3); 58.2 nM (VEGFR2) [1]Target: Flt3; Aurora Ain vitro: ENMD-2076 indicates activity against multiple kinases involved in angiogenesis, including FLT3, RET, FLT4/VEGFR3, SRC, NTRK1, CSF1R/FMS, LCK, VEGFR2/KDR, FGFR1/2, and PDGFRα with IC50 from 1.86-120 nM. ENMD-2076 inhibits the growth of a wide range of human solid tumor and hematopoietic cancer cell lines with IC50 from 0.025 to 0.7 μM, which induces apoptosis and G2/M phase arrest. ENMD-2076 induces regression or complete inhibition of tumor growth in tumor xenograft models derived from breast, colon, melanoma, leukemia, and multiple myeloma cell lines [1]. ENMD-2076 is the L (+) tartrate salt of ENMD-981693. ENMD-2076 shows significant cytotoxicity against myeloma cell lines (IM9, ARH-77, U266, RPMI 8226, MM.1S, MM.1R, NCI-H929) and primary cells with IC50 from 2.99 to 7.06 μM, which induces apoptosis. ENMD-2076 indicates low cytotoxicity to haematopoietic progenitors. ENMD-2076 inhibits the phosphoinositide 3-kinase/Akt pathway and downregulates survivin and X-linked inhibitor of apoptosis. ENMD-2076 also inhibits aurora A and B kinases, and induces G2/M cell cycle arrest [2].in vivo: ENMD-2076 has sustained inhibitory effects on the activation of Flt3 as well as VEGFR2/KDR and FGFR1/2 in HT29 xenograft model. ENMD-2076 could prevent the formation of new blood vessels and regress formed vessels in MDA-MB-231 xenograft model [1]. Oral treatment with ENMD-2076 (50, 100, 200 mg/kg per day) inhibits the tumour growth in H929 human plasmacytoma xenografts, with significant reduction in phospho-Histone 3 (pH3), Ki-67, and angiogenesis, and also a significant increase in cleaved caspase-3 [2].

SNS-314 is a potent and selective inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 9 nM, 31 nM, and 3 nM, respectively. IC50 Value: 9.0 nM(Aurora A); 31 nM(Aurora B); 3 nM(Aurora C)Target: pan Aurora Kinasein vitro: In HCT116 colorectal carcinoma cell line, with intact or depleted p53 protein levels, SNS-314 shows enhanced efficacy when administered sequentially with other standard chemotherapeutic agents and the most profound synergies are identified for agents that activate the spindle assembly checkpoint, e.g., docetaxel and vincristine. A recent study shows that SNS-314 shows potent antiproliferative activity in HCT116 cells and inhibits soft agar colony formation. in vivo: The sequential treatment with SNS-314 followed by docetaxel 24 hours later produces a significant 72.5% tumor growth inhibition of HCT116 xenografts, while docetaxel and SNS-314 as single agents produce no significant inhibition of HCT116 tumor growth. In the HCT116 human colon cancer xenograft model, administration of 50 and 100 mg/kg SNS-314 results a dose-dependent inhibition of histone H3 phosphorylation, indicating effective Aurora-B inhibition in vivo. In addition, HCT116 tumors from animals treated with SNS-314 exhibits potent and sustained responses including reduction of phosphorylated histone H3 levels, increased caspase-3 and appearance of increased nuclear size.

Doramapimod is a highly potent p38α inhibitor with an IC50 of 4 nM, also inhibits B-Raf with an IC50 of 83 nM and Abl with an IC50 of 14.6 μM.

Nilotinib is a second generation tyrosine kinase inhibitor (TKI), is significantly more potent against BCR-ABL than Imatinib, and is active against many Imatinib-resistant BCR-ABL mutants.

AST 487 is a RET kinase inhibitor with IC50 of 880 nM, inhibits RET autophosphorylation and activation of downstream effectors, also inhibits Flt-3 with IC50 of 520 nM.

Lck Inhibitor is a new class of compounds that are potent inhibitors of Lck with an IC50 value of 7 nM.IC50 Value: 7 nM [1]Target: Lckin vitro: Lck Inhibitor (compound 25) exhibited good potency in the T-cell receptor-induced IL-2 secretion assay (IL- 2) and also inhibited subsequent T-cell proliferation (T-cell prolif.) in the same human T -cells.in vivo: A once daily dose of 25was administered orally at 10, 30, and 60 mg/kg from day 9 today 17. Paw volume was measured daily from day 9 through day 18. The compound showed a dose-dependent inhibition of arthritis, with an ED50 estimated at 24 mg/kg (Figure 6). Based on the measured plasma levels from the three dose groups, the exposure of 25 at the ED50 was estimated to be 2.7 μM·h (Cmax≈ 0.7 μM) [1].Clinical trial: N/A

GDC-0068 dihydrochloride is a highly selective pan-Akt inhibitor targeting Akt1/2/3 with IC50 of 5/18/8 nM, 620-fold selectivity over PKA.

GZD824 is a novel orally bioavailable Bcr-Abl inhibitor for Bcr-Abl(WT) and Bcr-Abl(T315I) with IC50 of 0.34 nM and 0.68 nM, respectively. IC50 Value: 0.34/0.68 nM(Bce-Abl wt/T315I) [1]Target: Bcr-Abl in vitro: GZD824 potently suppressed proliferation of Bcr-Abl-positive K562 and Ku812 human CML cells with IC(50) values of 0.2 and 0.13 nM, respectively. It also displayed good oral bioavailability (48.7%), a reasonable half-life (10.6 h), and promising in vivo antitumor efficacy.in vivo: GZD824 induced tumor regression in mouse xenograft tumor models driven by Bcr-Abl(WT) or the mutants and significantly improved the survival of mice bearing an allograft leukemia model with Ba/F3 cells harboring Bcr-Abl(T315I) [1]. Clinical trial: GZD824 is on the way of unknown clinical status.

Ponatinib is a potent, orally available multi-targeted kinase inhibitor with IC50 of 0.37 nM, 1.1 nM, 1.5 nM, 2.2 nM, and 5.4 nM for Abl, PDGFRα, VEGFR2, FGFR1, and Src, respectively.

GSK1838705A is a potent small-molecule IGF-1R, the insulin receptor and anaplastic lymphoma kinase (ALK) inhibitor with IC50 of 2.0, 1.6 and 0.5 nM, respectively. IC50 value: 2.0/1.6/0.5 nM ( IGF-1R/InsR/ALK) Target: IGF-1R/InsR/ALKGSK1838705A prevents the in vitro proliferation of cell lines derived from solid and hematologic malignancies, including multiple myeloma and Ewing’s sarcoma, and retards the growth of human tumor xenografts in vivo. Despite the inhibitory effect of GSK1838705A on insulin receptor, minimal effects on glucose homeostasis were obtained at efficacious doses. A single oral dose of GSK1838705A at 0.1 and 0.3 mg/kg led to 35% and 65% prevention of IGF-IR phosphorylation, respectively, whereas doses ≥1 mg/kg led to complete inhibition of ligand-induced IGF-IR phosphorylation. Meanwhile, at a dose of 30 mg/kg, prevention was lasted for 24 hours after compound injection. GSK1838705A also suppresses the anaplastic lymphoma kinase (ALK), which mediates the aberrant growth of anaplastic large-cell lymphomas, some neuroblastomas, and a subset of non–small cell lung cancers. Due to its inhibition of ALK, GSK1838705A gives rise to complete regression of ALK-dependent tumors in vivo at well-tolerated doses.

CFI400945 is a potent and selective,orally bioavailable PLK4 inhibitor with an IC50 value of 2.8 ±1.4 nM have potential antineoplastic activity. target: PLK4[1]IC50：2.8 ±1.4 nM [3]In vitro: Cancer cells treated with CFI-400945 exhibit effects consistent with PLK4 kinase inhibition, including dysregulated centriole duplication, mitotic defects, and cell death.[1] CFI-400945 treatment lead to aberrant centriole duplication and abnormal mitoses in vitro that ultimately causes cell death or cell-cycle arrest. [2]In vivo: Oral administration of CFI-400945 to mice bearing human cancer xenografts results in the significant inhibition of tumor growth at doses that are well tolerated.[1]Oral administration of CFI-400945 was well tolerated in multiple xenograft models and mouse strains, and had favorable pharmacokinetics. CFI-400945 also had single-agent antitumor activity.[2]

GNF-5837 is a potent pan-Trk inhibitor which display antiproliferative effects in cellular Ba/F3 assays (IC50 values are 7, 9 and 11 nM for cells containing the fusion proteins Tel-TrkC, Tel-TrkB and Tel-TrkA, respectively).IC50 Value: 7/9/11 nM (Tel-TrkC/Tel-TrkB/Tel-TrkA) [1]Target: pan-TrkGNF-5837 is an orally bioavailable oxindole compound that and acts as a potent, reversible and type II DFG-out inhibitor of pan-Trk activity (IC50 = 8 and 12 nM for TrkA and TrkB). Shown to target Trk (tropomyosin receptor kinase) ATP binding cleft and an immediately adjacent hydrophobic pocket. Preferentially arrests the proliferation of Ba/F3 cells fused with Tel-TrkA, Tel-TrkB and Tel-TrkC (IC50 = 11, 9 and 7 nM, respectively) and in Ba/F3 and RIE cells expressing both TrkA and NGF (IC50 = 42 and 17 nM, respectively) over Mo7e-c-Kit and Rat-A10-PDGFR (IC50 = 1 and 0.5 μM) and Ba/F3-Tel-KDR and wt-Ba/F3 cells (IC50 = 3.0 and 5.6 μM). GNF-5837 displays ~100-fold greater selectivity among a panel of 59 closely related kinases and in 33 cellular kinase assays. GNF-5837 weakly antagonize relevant cytochrome P450 isozymes and hERG channel, and exhibit adequate microsomal stability, pharmacokinetic profile and efficacy in mice and rats. GNF-5837 suppresses tumor growth in a mouse RIE-TrkAmNGF xenograft model (50 mg/kg, p.o.) [1].

BIBF 1120 is a potent triple angiokinase inhibitor for VEGFR1/2/3, FGFR1/2/3 and PDGFRα/β with IC50s of 34 nM/13 nM/13 nM, 69 nM/37 nM/108 nM and 59 nM/65 nM, respectively.

XL147(SAR245408; pilaralisib) is a potent, orally bioavailable inhibitor of the class I PI3K family of lipid kinases with IC50 values of 39 nM/383 nM/36 nM/23 nM for PI3Kα/β/δ/γ, respectively; less potent to PI3Kβ.IC50 Value:39 nM (PI3Kα); 383 nM (PI3Kβ); 36 nM (PI3Kδ); 23 nM(PI3Kγ)[1]Target: in vitro: XL147 binds in an ATP-competitive and reversible manner, yet is highly selective against a panel of >130 human protein kinases. In cellular assays, XL147 antagonizes the production of the second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3) resulting in inhibition of phosphorylation of several downstream effectors of PI3K including Akt, ribosomal S6 kinase, and ribosomal S6 protein[1]. Compared with XL147 alone, the combination exhibited a superior antitumor effect against trastuzumab-resistant tumor xenografts. Furthermore, treatment with XL147 and trastuzumab reduced the cancer stem-cell (CSC) fraction within trastuzumab-resistant cells both in vitro and in vivo[2].in vivo: SAR245408 induced significant differences in EFS distribution compared to control in 29 of 37 (79%) of solid tumor xenografts and in two of seven (29%) ALL. Xenografts. SAR245408 induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity in 4 of 37 (11%) solid tumor xenografts[3].Toxicity: In vitro SAR245408 demonstrated cytotoxic activity, with a median relative IC50 value of 10.9 μM (range 2.7-24.5 μM)[4]. Clinical trial: Open-label Treatment Extension Study With SAR-245408 or SAR-245409 as a Monotherapy or as a Combination Regimen. Phase 1/Phase 2

Saracatinib is a potent Src inhibitor with IC50 of 2.7 nM, also inhibits EGFRL861Q (IC50=4nM), EGFRL858R (IC50= 5nM) and v-Abl (IC50=30 nM).CNX-2006 is a novel irreversible mutant-selective EGFR inhibitor with IC50 of < 20 nM, with very weak inhibition at wild-type EGFR.IC50 value: <20 nMTarget: Mutant EGFRCNX-2006 is a novel irreversible EGFR tyrosine kinase inhibitor, specifically inhibits activating mutations of EGFR as well as the T790M mutation while having very weak inhibition at wild-type EGFR. In in vitro modeling of acquired resistance, continuous CNX-2006 treatment on drug-sensitive EGFR mutant cells leads to resistance more slowly than erlotinib. Dose escalation with CNX-2006 leads to differential effects in different lines, but does not select for T790M-mediated resistance. CNX-2006 resistent cells shows increased expression of EMT markers and MMP9. CNX-2006 is effective in H1975 (EGFR L858R/T790M) xenograft model.

GNF-7 inhibits Bcr-Abl WT and Bcr-Abl T315I with IC50 of 133 nM and 61 nM, respectively. IC50 value: 133 nM (Bcr-Abl WT), 61 nM (Bcr-Abl T315I)Target: Bcr-Ablin vitro: GNF-7 is amongst the first type II inhibitors capable of inhibiting T315I to be described and will serve as a valuable lead to design next generation Bcr-Abl kinase inhibitors. GNF-7 exhibits some selectivity (4 to 100-fold) for T315I Bcr-Abl (IC50 = 11 nM, in Ba/F3 cell line) relative to kinases such as TPR-Met, NPM-ALK, JAK-3, Flt-3. in vivo: GNF-7 displays significant efficacy against T315I-Bcr-Abl without appreciable toxicity in a bioluminescent xenograft mouse model using a transformed T315I-Bcr-Abl-Ba/F3 cell line that has a stable luciferase expression. GNF-7 exhibits excellent pharmacokinetic parameters in mice, with good systemic exposure (AUC = 26656 hrs*nM, Cmax = 3.6 uM) along with reasonable half life (t1/2=3.2 hrs) and favorable oral bioavailability (BAV=36%) being observed following oral administration of a single dose of 20 mg/kg.

TAK-285 is a novel dual HER2 and EGFR(HER1) inhibitor with IC50 of 17 nM and 23 nM, >10-fold selectivity for HER1/2 than HER4, less potent to MEK1/5, c-Met, Aurora B, Lck, CSK etc. IC50 value: 17/23 nM (HER2/1) [1]Target: HER1/2in vitro: MEK1, MEK5, c-Met, Aurora B, Lck, CSK, and Lyn B with IC50 of 1.1 μM, 5.7 μM, 4.2 μM, 1.7 μM, 2.4 μM, 4.7 μM, and 5.2 μM, respectively, and displays no activity against other kinases with IC50 of >10 μM. TAK-285 shows significant growth inhibitory activity against BT-474 cells (HER2-overexpressing human breast cancer cell line) with GI50 of 17 nM [1]. Compared with SYR127063 a potent inhibitor of HER2, TAK-285 displays similar in vitro potency against HER2 and EGFR. Compared with the full cytoplasmic domains of the wild-type proteins, the mutations and shortened boundaries used for structure determination of HER2-KD and EGFR-KD do not significantly change the inhibitory activity (IC50) of TAK-285. TAK-285 binds to the inactive conformation of EGFR, and shows a similar binding mode with lapatinib in the active site [2]. in vivo: The oral bioavailability of TAK-285 is 97.7% in rats and 72.2% in mice at a dose of 50 mg/kg. Oral administration of TAK-285 at 100 mg/kg twice daily for 14 days displays significant antitumor efficacy in the HER2-overexpressing BT-474 tumor xenograft mouse model with tumor/control (T/C) ratio of 29%, without affecting body weight. Similar to the BT-474 model, TAK-285 exhibits dose-dependent tumor growth inhibition of 4-1ST (HER2-overexpressing human gastric cancer tumor) xenografts in mice, with T/C of 44% and 11% at doses of 50 mg/kg and 100 mg/kg, twice daily, respectively, without significant body weight loss in mice [1]. After oral administration of TAK-285, a significant amount of TAK-285 is present in the brain of rats in pharmacologically active, unbound form (approximately 20% of its free plasma level), indicating that TAK-285 has a potential in the therapy of CNS malignancies/metastases [3].

Neratinib is an orally available, irreversible tyrosine kinase inhibitor with IC50s of 59 nM and 92 nM for HER2 and EGFR, respectively.

THZ1 is a selective and potent covalent CDK7 inhibitor with IC50 of 3.2 nM.

SU11274 is a selective Met inhibitor with IC50 of 10 nM, but has no effects on PGDFRβ, EGFR or Tie2

GSK269962A is a potent ROCK inhibitor with IC50s of 1.6 and 4 nM for recombinant human ROCK1 and ROCK2 respectively.

Belizatinib is an oral, dual, potent inhibitor of ALK and TRKA, TRKB, and TRKC, with IC50 of 0.7 nM for wild-type recombinant ALK kinase.

ASP3026 is a novel and selective inhibitor for ALK (anaplastic lymphoma kinase) with IC50 of 3.5 nM.

Brigatinib is a highly potent and selective ALK inhibitor, with IC50 of 0.6 nM.

Pluripotin (SC-1) inhibits in vitro kinase activity of RSK2 with EC50 of 2.5±1.8 μM.IC50 value: 2.5±1.8 μM (EC50)Target: RSK2in vitro: Pluripotin, a dual kinase and GTPase inhibitor that promotes self-renewal, and then examined for tumorigenicity under limiting dilution conditions and clonogenic activity in soft agar. Pluripotin is inhibitory for p70S6K (IC50 = 1.4 μM ).

CCT 137690 is a potent inhibitor of Aurora kinases (IC50 values are 0.015, 0.019 and 0.025 μM at Aurora A, Aurora C and Aurora B respectively). IC50 Value: 15 nM (Aurora A); 25 nM (Aurora B); 19 nM (Aurora C)Target: pan Aurora Kinasein vitro: CCT137690 displays antiproliferative activity in a range of human tumor cell lines, including SW620 colon carcinoma cell and A2780 ovarian cancer cell with GI50 of 0.3 and o.14 μM, respectively. In addition, CCT137690 also inhibit the phosphorylation of histone H3. CCT137690 inhibits the major cytochrome P450 isoforms (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP3A4) with IC50 greater than 10 μM. However, CCT137690 is a moderate inhibitor of the hERG ion-channel with IC50 of 3.0 μM. CCT137690 inhibits autophosphorylation of FLT3 and phosphorylation of its downstream targets STAT5 and p44/42 MAPK (Erk1/2). CCT137690 effectively inhibits the growth of human tumor cell lines of different origins with GI50 ranging from 0.005 to 0.47 μM. CCT137690 completely inhibits both Aurora A autophosphorylation at T288 and histone H3 phosphorylation at 0.5 μM. CCT137690 induces polyploidy, mitotic aberrations, and apoptosis in HCT116 cells. CCT137690 reduces MYCN levels and GSK3β phosphorylation in the KELLY neuroblastoma cell line. in vivo: CCT137690 inhibits growth of MYCN-induced neuroblastoma at a dose of 100 mg/kg. Additionally, CCT137690 achieves target modulation and potently inhibits the growth of subcutaneous MOLM-13 xenografts, with no obvious toxicity or loss of body weight. CCT137690 is highly orally bioavailable and inhibits the growth of SW620 colon carcinoma xenografts with no observed toxicities as defined by body weight loss.

AKT inhibitor VIII is a cell-permeable quinoxaline compound that has been shown to potently, selectively, allosterically, and reversibly inhibit Akt1, Akt2, and Akt3 activity with IC50s of 58 nM, 210 nM, and 2.12 μM, respectively.LY2801653 is a type-II ATP competitive, slow-off inhibitor of MET tyrosine kinase with a dissociation constant (Ki) of 2 nM.DDR1-IN-1 is a potent and selective DDR1 receptor tyrosine kinaseinhibitor with IC50/EC50 of 105 nM/87 nM; 4-fold less potent for DDR2 (IC50= 413 nM).IC50 value: 105 nM [1]Target: DDR1We confirmed the observed binding to DDR1 using an enzymatic kinase assay employing the Lanthascreen technology. In this assay DDR1-IN-1 exhibits an IC50 of 105 nM against DDR1 and 413 nM against DDR2. DDR1-IN-1 and DDR1-IN-2 inhibited basal DDR1 autophosphorylation with an EC50 of 86 nM and 9 nM, respectively. Both DDR1-IN-1 and DDR1-IN-2 demonstrated weaker inhibition of DDR1 autophosphorylation in the absence of collagen stimulation.

LEE011 succinate is a highly specific CDK4/6 inhibitor with IC50 values of 10 nM and 39 nM, respectively, and is over 1,000-fold less potent against the cyclin B/CDK1 complex.DCC-2036 is a conformational control Bcr-Abl inhibitor for Abl1WT and Abl1T315I with IC50 of 0.8 nM and 4 nM, also inhibits SRC, KDR, FLT3, and Tie-2, and low activity to seen towards c-Kit. Ro 31-8220 mesylate (Bisindolylmaleimide IX) is a pan-PKC inhibitor with IC50 of 5 nM, 24 nM, 14 nM, 27 nM, and 24 nM for PKC-α, PKC-βI, PKC-βII, PKC-γ, and PKC-ε, respectively.IC50 Value: 5, 24, 14, 27, and 24 nM (PKC α, PKC βI, PKC βII, PKC γ, and PKC) [1]Target: pan-PKCRo 31-8220, a staurosporine (sc-3510) analog, is a cell-permeable inhibitor of PKC (protein kinase C) isoforms PKC α, PKC βI, PKC βII, PKC γ, and PKC ε (IC50 = 5, 24, 14, 27, and 24 nM, respectively). Ro 31-8220 has also been shown to induce apoptosis in various cell lines, independent of its PKC activity, and to inhibit GSK 3 (IC50 = 6.8nM). Ro 31-8220 is an inhibitor of Cdk2, cyclin A, GSK-3β, MSK1, Pim-3, Polycystin-1, PRK2, Rsk-1 and Rsk-2 and an activator of JNK1.Ro 31-8220 antagonized (IC50, 1.0 microM) the effect of the activator of protein kinase C,12-O-tetradecanoylphorbol 13-acetate (TPA), on histamine-stimulated aminopyrine accumulation. Ro 31-8220 (0.1-2.14 microM) inhibited the aminopyrine response to 0.1 mM carbachol (IC50, 0.78 microM; 49% inhibition at 2.14 microM Ro 31-8220) and shifted the dose-response curve for the effect of carbachol concentration of aminopyrine accumulation downwards and to the right. No inhibition of aminopyrine accumulation induced by histamine was found with Ro 31-8220 (0.1-2.14 microM) [1]. U-87 and A172 cells treated with an IC50 of Ro 31-8220 exhibited nucleosomal DNA fragmentation that coincided with an increase in the number of apoptotic cells. This effect was preceded by the rapid nuclear accumulation of wild-type p53 within 2 hr, and an increased level of the pro-apoptotic protein, insulin-like growth factor-1-binding protein-3, (IGFBP3) but not other p53-regulated proteins such as p21WAF1 or Bax [2].

TAK-632 is a potent pan-RAF inhibitor with IC50 of 1.4, 2.4 and 8.3 nM for CRAF, BRAFV600E, BRAFWT, respectively.CO-1686 is an orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR including T790M, and the IC50 values for EGFRL858R/T790M and EGFRWT are 21.5 nM and 303.3 nM, respectively.

CGK 733 is a small molecule inhibitor reportedly targeting the kinase activities of ATM and ATR.IC50 Value: Target: ATM/ATRin vitro: Culture of MCF-7 breast cancer cells with 10 μM CGK733 induced a detectable decline of cyclin D1 levels within 2 h of exposure, and this effect was maximal between 4 and 6 h after exposure, CGK733 induced the loss of cyclin D1 expression at concentrations as low as 5 μM and this activity was maximal at 10 to 20 μM The CGK733 induced attenuation of cyclin D1 levels was inhibited by the 26S proteasome inhibitor MG132 but not the GSK3β inhibitor lithium chloride (LiCl) in MCF-7 and T47D cells [1]. CGK733 significantly enhanced taxol-induced cytotoxicity in HBV-positive HepG2.2.15 cells. The mechanism lies in CGK733 triggers the formation of multinucleated cells thus promotes the premature mitotic exit of taxol-induced mitotic-damaged cells through multinucleation and mitotic catastrophe in HBV-positive HepG2.2.15 cells [2].LDK378 is a potent and more specific ALK inhibitor with IC50 of 0.2 nM.SU14813 maleate is an oral, multitargeted tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptors (PDGFR), Kit, and fms-like tyrosine kinase 3 (FLT-3).IC50 value:Target: VEGFR/PDGFR/Flt-3/kitSU14813 was developed as a next-generation TKI agent following sunitinib (SU11248) designed to demonstrate optimized pharmacokinetic (PK) and tolerability profiles. SU14813 demonstrated broad and potent antitumor activity equivalent to that of sunitinib, which resulted in tumor regression, growth arrest, growth delay, and prolonged survival in established xenograft cancer models in mice.

Canertinib 2Hcl (CI-1033; PD-183805) is a pan-ErbB inhibitor for EGFR and ErbB2 with IC50 of 1.5 nM and 9.0 nM, no activity to PDGFR, FGFR, InsR, PKC, or CDK1/2/4.IC50 value: 1.5/0.9 nM(EGFR/ErbB2) [1]Target: EGFR/ErbB2in vitro: CI-1033 shows excellent potency for irreversible inhibition of erbB2 autophosphorylation in MDA-MB 453 cells. CI-1033 also shows high permeability in Caco-2 cells and inhibits secretory transport of vinblastine, which indicates that CI-1033 is a likely inhibitor of the P-gp [1]. CI-1033 alone, significantly suppresses constitutively activated Akt and MAP kinase. In combination with gemcitabine, CI-1033 inhibits Akt and prevents increased levels of MAPK phosphorylation. CI-1033 stimulates p27 expression and p38 phosphorylation in MDA-MB-453 cells [2]. CI-1033 is highly specific to the erbB receptor family and not sensitive to PGFR, FGFR or IR even at 50 μM. CI-1033 shows high levels of inhibition in A431 cells expressing EGFR with IC50 of 7.4 nM. CI-1033 suppresses heregulin-stimulated tyrosine phosphorylation of erbB2, erbB3 and erbB4 with IC50 of 5, 14 and 10 nM, respectively. CI-1033 also inhibits expression of pp62c-fos in response to heregulin [3]. in vivo: CI-1033 shows impressive activity against A431 xenografts in nude mice at 5 mg/kg of body weight [1]. CI-1033 (20 to 80 mg/kg/d) achieves a high degree of tumor regressions in H125 xenograft models [3]. Oral administration of CI-1033 causes a marked inhibition of growth in TT, TE6 and TE10 xenografts in nude mice, without animal death and <10% weight loss [4].

NVP-BGJ398 is a potent inhibitor of the FGFR family with IC50 of 0.9 nM, 1.4 nM, 1 nM, and 60 nM for FGFR1, FGFR2, FGFR3, and FGFR4, respectively.

LDC1267 is a highly selective TAM(Tyro3, Axl and Mer) kinase inhibitor with IC50 of <5 nM/8 nM/29 nM for Tyro3,Axl and Mer respectively.IC50 value: <5 nM/8 nM/29 nM(Tyro3/Axl/Mer) [1]Target: TAM kinase inhibitorin vitro: LDC1267 preferentially inhibits Tyro3,Axl andMer at lownanomolarity, as determined by tracer-based binding assays. Treatment of NKG2D activated NK cells with LDC1267 indeed abolished the inhibitory effects of Gas6 stimulation;LDC1267 had no apparent additional effect in Cbl-b-deficient NK cells. in vivo: wild-type mice treated with LDC1267 showed enhanced cytotoxicity towardsRMAcells overexpressing the NKG2D ligand Rae-1 (RMA-Rae1) to the same extent as C373AKI/KI mice, but had no effect on the already enhanced NK cytotoxicity in Cbl-b-mutant mice. Challenged mice with B16F10 melanoma followedby intraperitoneal LDC1267 treatment. LDC1267 markedly reduced metastatic spreading ofmelanomas; NK1.1 depletion abolished the therapeutic benefits of LDC1267.

Entrectinib is a potent and orally available Trk, ROS1, and ALK inhibitor; inhibits TrkA, TrkB, TrkC, ROS1 and ALK with IC50 values of 1, 3, 5, 12 and 7 nM, respectively.Quizartinib is a uniquely potent and selective Flt3 inhibitor with Kd (FLT3 binding affinity) of 1.6±0.7 nM in Biochemical assay.PD318088 is a non-ATP competitive allosteric MEK1/2 inhibitor, binds simultaneously with ATP in a region of the MEK1 active site that is adjacent to the ATP-binding site.IC50 value:Target: MEK1/2in vitro: PD318088 is a small-molecule inhibitor of MEK1/2, which is an analog of PD184352, suggesting it might have substantial anti-proliferative activity against cancer cells, although no functional study of PD318088 is currently available. PD318088 binds simultaneously with ATP in a region of the MEK1 active site that is adjacent to the ATP-binding site. Formation of the ternary complexes with PD318088 and MgATP results in moderate increases (to 140 nM) for the Kd monomer-dimer for both MEK1 and MEK2. The binding of PD318088 and MgATP to MEK1 also abolishes the formation of tetramers and higher-order aggregates. PD318088 and MgATP together increase the dimerization disassociation constant for MEK1 and MEK2 slightly from ~75 nM to ~140 nM, suggesting that the mechanism of inhibition for PD318088 is probably a result of localized conformational changes in the active site and not a global change in the overall structure.

TAK-960 is a novel, investigational, orally bioavailable, potent, and selective PLK1 inhibitor(IC50=1.5 nM) that has shown activity in several tumor cell lines, including those that express multidrug-resistant protein 1 (MDR1).IC50 value: 1.5 nMTarget: PLK1in vitro: Consistent with PLK1 inhibition, TAK-960 treatment caused accumulation of G2–M cells, aberrant polo mitosis morphology, and increased phosphorylation of histone H3 (pHH3) in vitro and in vivo. TAK-960 inhibited proliferation of multiple cancer cell lines, with mean EC50 values ranging from 8.4 to 46.9 nmol/L, but not in nondividing normal cells (EC50 >1,000 nmol/L). The mutation status of TP53 or KRAS and MDR1 expression did not correlate with the potency of TAK-960 in the cell lines tested.in vivo: In animal models, oral administration of TAK-960 increased pHH3 in a dose-dependent manner and significantly inhibited the growth of HT-29 colorectal cancer xenografts. Treatment with once daily TAK-960 exhibited significant efficacy against multiple tumor xenografts, including an adriamycin/paclitaxel-resistant xenograft model and a disseminated leukemia model.

Flumatinib is a multi-kinase inhibitor with IC50 Values of 1.2 nM, 307.6 nM and 2662 nM for c-Abl, PDGFRβ and c-Kit respectively.IC50 Value: 1.2 nM (c-Abl); 307.6 nM(PDGFRβ); 2662 nM (c-Kit) [1]Target: c-Abl; c-Kit; PDGRFβin vitro: HH-GV-678 can predominantly inhibit the autophosphorylation of Bcr-Abl in K562 cell. In higher concentration, HH-GV-678 can inhibit the phosphorylation of c-Kit in Mo7e cell and the phosphorylation of PDGFR in Swiss3T3 cell, however, HH-GV-678 has no or little effect on other tyrosine kinase including EGFR, KDR, c-Src and HER2 [1]. Flumatinib effectively overcame the drug resistance of certain KIT mutants with activation loop mutations (i.e., D820G, N822K, Y823D, and A829P) [2].in vivo: The purpose of this study was to identify the metabolites of flumatinib in CML patients, with the aim of determining the main metabolic pathways off lumatinib in humans after oral administration. Ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry revealed 34 metabolites; 7 primary metabolites were confirmed by comparison with synthetic reference standards. The results show that the parent drugflumatinib was the main form recovered in human plasma, urine, and feces. The main metabolites of flumatinib in humans were the products of N-demethylation, N-oxidation, hydroxylation, and amide hydrolysis [3].

Tandutinib (MLN518, CT53518) is a potent FLT3 antagonist with IC50 of 0.22 μM, also inhibits PDGFR and c-Kit, 15 to 20-fold higher potency for FLT3 versus CSF-1R and >100-fold selectivity for the same target versus FGFR, EGFR and KDR. IC50 value: 0.22 uM [1]Target: Flt3; PDGFRβ; c-Kitin vitro: Tandutinib has little activity against EGFR, FGFR, KDR, InsR, Src, Abl, PKC, PKA and MAPKs. Tandutinib inhibits IL-3-independent cell growth and FLT3-ITD autophosphorylation with an IC50 of 10-100 nM. Tandutinib also inhibits the proliferation of human leukemia Ba/F3 cells containing FLT3-ITD mutations with IC50 values of 10-30 nM, and the FLT3-ITD-positive Molm-13 and Molm-14 cells with an IC50 of 10 nM. In FLT3-ITD-positive Molm-14 cells but not the FLT3-ITD-negative THP-1 cells, Tandutinib treatment leads to significant apoptosis by 51% and 78% at 24 and 96 hours, respectively, due to specific FLT3 inhibition [1]. Tandutinib preferentially inhibits the growth of blast colonies from FLT3 ITD-positive compared with ITD-negative patients with AML, without affecting colony formation by normal human progenitor cells [2].in vivo: Oral administration of Tandutinib at 60 mg/kg bid significantly increases the survival in mice bearing Ba/F3 cells expressing W51 FLT3-ITD mutant, and gives a significant reduction in mortality in a mouse bone marrow transplantation model [1]. Tandutinib treatment at 180 mg/kg twice daily has mild toxicity toward normal hematopoiesis, however, it is a dose at which Tandutinib is effective in treating FLT3 ITD-positive leukemia in mice [2].

Cediranib (AZD2171) maleate is a highly potent VEGFR(KDR) inhibitor with IC50 of <1 nM, also inhibits Flt1/4 with IC50 of 5 nM/≤3 nM, similar activity against c-Kit and PDGFRβ, 36-, 110-fold and >1000-fold selective more for VEGFR than PDGFR-α, CSF-1R and Flt3.IC50 value: 0.5 nM (VEGFR2); 5 nM/≤3 nM(Flt1/4) [1]Target: VEGFR2; Flt1/4in vitro: Cediranib maleate inhibits VEGF-stimulated proliferation with IC50 of 0.4 nM. Cediranib suppresses PDGF-AA with IC50 of 0.04 μM in MG63 cell lines. Cediranib has been shown to block Flt1-associated kinase with IC50 of 5 nM and VEGF-C and VEGF-D receptor Flt-4 with IC50 less than 3 nM. In addition, the IC50 values for inhibition of c-Kit and PDGFRβ tyrosine kinase are 2 nM and 5 nM respectively. Furthermore, no inhibition of enzyme activity is observed when 10 μM Cediranib is assayed with 100 μM ATP against AMPK, Chk1 Akt/PKB and others. Micromolar concentrations of Cediranib are needed to prevent tumor cell proliferation in vitro [1].in vivo: Cediranib even suppresses tubule sprouting at subnanomolar concentrations and inhibits VEGF-induced angiogenesis. Cediranib causes hypertrophy in bone growth plate and prevents luteal development in ovary. These are physiological processes that are dependent upon angiogenesis. Cediranib shows broad spectrum activity in human tumor models at doses that are well tolerated [1]. Besides, Cediranib causes regression of vascular tissues in human lung tumor xenografts [2].

AC480 (BMS-599626) is a selective and efficacious inhibitor of HER1 and HER2 with IC50 of 20 nM and 30 nM, ~8-fold less potent to HER4, >100-fold to VEGFR2, c-Kit, Lck, MET etc.IC50 value: 20 nM (HER1); 30 nM (HER2) [1]Target: HER1/HER2in vitro: BMS-599626 inhibited HER1 and HER2 with IC50 of 20 and 30 nmol/L, respectively, and was highly selective when tested against a broad panel of diverse protein kinases. Biochemical studies suggested that BMS-599626 inhibited HER1 and HER2 through distinct mechanisms. BMS-599626 abrogated HER1 and HER2 signaling and inhibited the proliferation of tumor cell lines that are dependent on these receptors, with IC50 in the range of 0.24 to 1 micromol/L. BMS-599626 was highly selective for tumor cells that depend on HER1/HER2 and had no effect on the proliferation of cell lines that do not express these receptors. In tumor cells that are capable of forming HER1/HER2 heterodimers, BMS-599626 inhibited heterodimerization and downstream signaling [1]. At the molecular level, in HN-5 cells the agent inhibited the expression of pEGFR, pHER2, cyclins D and E, pRb, pAkt, pMAPK, pCDK1 and 2, CDK 6, and Ku70 proteins. The drug also induced accumulation of cells in the G1 cell cycle phase, inhibited cell growth, enhanced radiosensitivity, and prolonged the presence of γ-H AX foci up to 24 h after radiation [2].in vivo: BMS-599626 had antitumor activity in models that overexpress HER1 (GEO), as well as in models that have HER2 gene amplification (KPL4) or overexpression (Sal2), and there was good correlation between the inhibition of receptor signaling and antitumor activity [1]. The drug given before and during irradiation improved the radioresponse of HN5 tumors in vivo [2].

WH-4-023 is a potent and selective dual Lck/Src inhibitor with IC50 of 2 nM/6 nM for Lck and Src kinase respectively; little inhibition on p38α and KDR. Motesanib diphosphate (AMG-706) is a potent ATP-competitive inhibitor of VEGFR1/2/3 with IC50 of 2 nM/3 nM/6 nM, respectively; similar activity against Kit, ~10-fold more selective for VEGFR than PDGFR and Ret.IC50 value: 2 nM/3 nM/6 nM/8 nM(VEGFR1/2/3/c-Kit) [1]Target: pan-VEGFR; Kitin vitro: Motesanib Diphosphate has broad activity against the human VEGFR family, and displays >1000 selectivity against EGFR, Src, and p38 kinase. Motesanib Diphosphate significantly inhibits VEGF-induced cellular proliferation of HUVECs with an IC50 of 10 nM, while displaying little effect at bFGF-induced proliferation with an IC50 of >3,000 nM. Motesanib Diphosphate also potently inhibits PDGF-induced proliferation and SCF-induced c-kit phosphorylation with IC50 of 207 nM and 37 nM, respectively, but not effective against the EGF-induced EGFR phosphorylation and cell viability of A431 cells [1]. Althouth displaying little antiproliferative activity on cell growth of HUVECs alone, Motesanib Diphosphate treatment significantly sensitizes the cells to fractionated radiation [2].in vivo: Administration of Motesanib Diphosphate at 100 mg/kg significantly inhibits VEGF-induced vascular permeability in a time-dependent manner. Oral administration of Motesanib Diphosphate twice daily or once daily potently inhibits, in a dose-dependent manner, VEGF-induced angiogenesis using the rat corneal model with ED50 of 2.1 mg/kg and 4.9 mg/kg, respectively. Motesanib Diphosphate induces a dose-dependent tumor regression of established A431 xenografts by selectively targeting neovascularization in tumor cells [1]. Administration of Motesanib Diphosphate in combination with radiation displays significant anti-tumor activity in head and neck squamous cell carcinoma (HNSCC) xenograft models [2]. Motesanib Diphosphate treatment also induces significant dose-dependent reductions in tumor growth and blood vessel density of MCF-7, MDA-MB-231, or Cal-51 xenografts, which can be markedly enhanced when combined with docetaxel or tamoxifen [3].

LEE011 succinate hydrate is a highly specific CDK4/6 inhibitor with IC50 values of 10 nM and 39 nM, respectively, and is over 1,000-fold less potent against the cyclin B/CDK1 complex.TGR-1202 is a novel PI3Kδ inhibitor, with IC50 and EC50 of 22.2 nM and 24.3 nM, respectively; Also active against CK1ε, with an EC50 value of 6.0 μM.

Refametinib (RDEA119, BAY 86-9766), is an orally bioavailable selective MEK inhibitor with potential antineoplastic activity (IC50=19 nM MEK1; IC50=47 nM MEK2).IC50 Value: 19 nM (MEK1); 47 nM (MEK2) [1]Target: MEK1; MEK2in vitro: RDEA119 potently inhibited MEK activity in enzyme inhibition assays in a non-ATP-competitive manner (MEK1 IC50 = 19 nmol/L, MEK2 IC50 = 47 nmol/L) determined through incorporation of radioactive phosphate from ATP into ERK as substrate. RDEA119 potently inhibited MEK activity as measured by phosphorylation of ERK1/2 across several human cancer cell lines of different tissue origins and BRAF mutational status with EC50 values ranging from 2.5 to 15.8 nmol/L [1]. BAY 86-9766 exhibited potent antiproliferative activity in HCC cell lines with half-maximal inhibitory concentration values ranging from 33 to 762 nM. BAY 86-9766 was strongly synergistic with sorafenib in suppressing tumor cell proliferation and inhibiting phosphorylation of the extracellular signal-regulated kinase (ERK) [2]. in vivo: RDEA119/BAY 869766 exhibits potent activity in xenograft models of melanoma, colon, and epidermal carcinoma. RDEA119/BAY 869766 exhibits complete suppression of ERK phosphorylation at fully efficacious doses in mice. RDEA119/BAY 869766 shows a tissue selectivity that reduces its potential for central nervous system-related side effects [1]. BAY 86-9766 prolonged survival in Hep3B xenografts, murine Hepa129 allografts, and MH3924A rat allografts. Additionally, tumor growth, ascites formation, and serum alpha-fetoprotein levels were reduced. Synergistic effects in combination with sorafenib were shown in Huh-7, Hep3B xenografts, and MH3924A allografts [2].

Palbociclib (isethionate) is a highly selective inhibitor of CDK4/6 with IC50s of 11 nM/16 nM, and shows no activity against CDK1/2/5, EGFR, FGFR, PDGFR, InsR, etc. CHIR-99021 trihydrochloride is a GSK-3α/β inhibitor with IC50 of 10 nM/6.7 nM; > 500-fold selectivity for GSK-3 versus its closest homologs CDC2 and ERK2, as well as other protein kinases.

Bafetinib (INNO-406) is a potent and selective dual Bcr-Abl/Lyn inhibitor with IC50 of 5.8 nM/19 nM in cell-free assays.IC50 value: 5.8 nM/19 nM [2]Target: Bcr-Abl/Lynin vitro: Bafetinib (1-10 μM) concentration dependently inhibits PAR2-TRPV4 coupling. In TRPV4 HEKs, 10 μM Bafetinib significantly inhibits the coupling response to SLIGRL and trypsin compared with vehicle control. Bafetinib inhibits the signalling pathway leading to TRPV4 channel opening, downstream of PAR2 activation, most likely by blocking the activation of a tyrosine kinase. [1] Bafetinib blocks WT Bcr-Abl autophosphorylation and its downstream kinase activity with IC50 of 11 nM and 22 nM in K562 and 293T cells, respectively. Bafetinib suppresses the growth of the Bcr-Abl-positive cell lines including K562, KU812, and BaF3/wt cells potently without effects on the proliferation of the Bcr-Abl-negative U937 cell line. Moreover, Bafetinib exhibits a dose-dependent antiproliferative effect against Bcr-Abl point mutant cell lines, such as BaF3/E255K cells. [2] in vivo: In Bcr-Abl-positive KU812 mouse model, Bafetinib (0.2 mg/kg/day) significantly inhibits tumor growth, and completely inhibits tumor growth without adverse effects at 20 mg/kg/day. For Balb/c mice, Bafetinib shows maximal tolerated dose of 200 mg/kg/d and bioavailability value (BA) of 32%.[2]CGI-1746 is a potent and highly selective inhibitor of the Btk with IC50 of 1.9 nM.CEP-37440 is a novel potent and selective Dual FAK/ALK inhibitor with IC50 s of 2.3 nM (FAK) and 120 nM(ALK cellular IC50 in 75% human plasma).IC50 value: 2.3 nM (FAK); 120 nM (ALK cellular IC50 in 75% human plasma)Target: Dual FAK/ALKPreparation of fused bicyclic 2,4-diaminopyrimidine derivatives as a dual ALK and FAK inhibitorBy Jacobs, Martin J.; Ott, Gregory R. From PCT Int. Appl. (2013), WO 2013134353 A1 20130912.Lapatinib is a potent EGFR and ErbB2 inhibitor with IC50 of 10.2 and 9.8 nM, respectively. Nilotinib monohydrochloride monohydrate is a second generation tyrosine kinase inhibitor (TKI), is significantly more potent against BCR-ABL than Imatinib, and is active against many Imatinib-resistant BCR-ABL mutants.

AZD1152 is a pro-drug of barasertib-hQPA, which is a highly selective Aurora B inhibitor with IC50 of 0.37 nM in a cell-free assay.

BX795 is a potent and selective dual inhibitor of TBK1/PDK1 with IC50s of 2 nM/6 nM, respectively, and has > 50 fold selectivity over PKA, PKC, c-Kit, GSK3β etc.

Masitinib mesylate is a novel inhibitor for Kit and PDGFRα/β with IC50 of 200 nM and 540 nM/800 nM, and has weak inhibition to ABL and c-Fms.

PI3K-IN-1 is a potent inhibitor of PI3K, more information can be found in patent WO2012103524 A2 and WO2013147649 A2.THZ1 Hydrochloride is a selective and potent covalent CDK7 inhibitor with IC50 of 3.2 nM.LY2835219 a selective CDK4/6 inhibitor with IC50 values of 2 nM and 10 nM for CDK4 and CDK6, respectively.Avitinib maleate is a pyrrolopyrimidine-based irreversible epidermal growth factor receptor (EGFR) inhibitor with an IC50 of 7.68 nM.

Neohesperidin dihydrochalcone is a synthetic glycoside chalcone, is added to various foods and beverages as a low caloric artificial sweetener.

NVP-TAE 684 is a highly potent and selective ALK inhibitor, which blocks the growth of ALCL-derived and ALK-dependent cell lines with IC50 values between 2 and 10 nM.Trametinib is a potent MEK1/2 inhibitor that specifically inhibits MEK1/2, with an IC50 value of about 2 nM.

Centrinone is a selective and reversible inhibitor of polo-like kinase 4 (PlK4) with a Ki of 0.16 nM.

Sorafenib tosylate is a potent multikinase inhibitor, with IC50s of 6 nM, 20 nM, and 22 nM for Raf-1, B-Raf, and VEGFR-3, respectively.XMD17-109 is a novel, specific ERK-5 inhibitor, which inhibits the ERK5-mediated AP1 transcriptional activity at 30 μM, and has an EC50 of 4.2 μM.

CFI-400945 fumarate is a potent, selective and orally bioavailable PLK inhibitor with a Ki of 0.26 nM.

Aurora A inhibitor I is a selective Aurora A inhibitor (Aurora A: IC50=0.0034 μM; Aurora B IC50=3.4 μM), (B/A ratio=1000).IC50 value: 3.4 nMTarget: Aurora AAurora A inhibitor I is an exceptionally selective Aurora A inhibitor; we can see no indications in cellular assays that it inhibits Aurora B or CDKs. As such, it is a useful tool compound for investigating the cellular role of Aurora A kinases without the complication of also inhibiting Aurora B.Imatinib Mesylate is a known inhibitor of the c-Kit, Bcr-Abl, and PDGFR tyrosine kinases, inhibits the SLF-dependent activation of c-Kitwt kinase with IC50 of ~100 nM, which is similar to the concentration requires for inhibition of Bcr-Abl and PDGFR.A 419259 trihydrochloride is a broad-spectrum pyrrolo-pyrimidine inhibitor, designed to enhance selectivity towards the Src family with IC50 of 9 nM, <3 nM and <3 nM for Src, Lck and Lyn, respectively.

AZD-9291 mesylate is a third generation irreversible EGFR tyrosine kinase inhibitor with selectivity against mutant versus wild-type forms of EGFR, shows an apparent IC50 of 12 nM against L858R and 1 nM against L858R/T790M in EGFR recombinant enzyme assay.

KRCA-0008 is a potent and selective ALK/Ack1 inhibitor with IC50 of 12 nM/4 nM for ALK and Ack1 respectively; displays drug-like properties without hERG liability.IC50 value: 12 nM/4 nM(ALK/Ack1) [1]Target: ALK/Ack1 inhibitorKRCA-0008 retains good drug-like properties: good water-solubility (54 μM in 5% DMSO–water, 150 μM in 5% DMSO–PBS buffer) with moderate plasma protein binding (93% in rat) and low brain exposure (Cbrain/Cplasma = ～0.02). It has good liver microsomal stability (% remaining after 30 min: 52% in mouse, 89% in rat, 72% in human) and little to no CYP inhibition (1A2, 2C9, 2D6, 3A4 @ 10 μM). It does not appear to cause hERG blockade (patch clamp IC50 = 30 μM) and is negative on Ames test (1000 μg/plate), chromosomal aberration assay and micronucleus assay.KRCA-0008 also shows promising pharmacokinetic parameters in both mice and rat (oral bioavailability = 66–94.5%). KRCA-0008 shows a modest tumor growth inhibition in vivo activity in H3122 human lung cancer bearing mice model comparable to Crizotinib without significant body weight change. It is important to mention the KRCA-0008 25 mpk and 50 mpk groups did not show dose-dependent tumor growth inhibition.

EG00229 is the first small molecule inhibitor of the neuropilin-1 and VEGF-A interaction with an IC50 of inhibition of 8 uM(125I-VEGF binding to PAE/NRP1 cells).IC50 value: 8 uM [1]Target: NRP1/VEGF-A inhibitorEG00229 reduced VEGF-A-induced VEGFR2 tyrosine phosphorylation in HUVECs in a dose-dependent fashion, with a maximum inhibition of 34% at 100 μM. EG00229 also significantly reduced VEGF-A induced migration of HUVECs. caused a partial inhibition of VEGF receptor activity and biological function, consistent with the current model for the role of NRP1 in VEGF function, in which NRP1 is required for optimal signaling and certain biological functions downstream of VEGFR2, particularly migration [1].LY2228820 is a novel and potent inhibitor of p38 MAPK with IC50 of 7 nM in a cell-free assay, but does not alter p38 MAPK activation.

Dabrafenib (Mesylate) is a novel, potent, and selective Raf kinase inhibitor, and inhibits the kinase activity of B-RafV600Eand c-Raf with IC50 values of 0.6 and 5.0 nM, respectively.LY-2584702 tosylate salt is an orally available inhibitor of p70S6K signaling; inhibits p70S6K and prevents phosphorylation of the S6 subunit of ribosomes.IC50 value:Target: p70S6K inhibitorLY-2584702 is an orally available inhibitor of p70S6K signaling, with potential antineoplastic activity. LY2584702 inhibits ribosomal protein S6 Kinase (p70S6K), and prevents phosphorylation of the S6 subunit of ribosomes, thereby inhibiting normal ribosomal function within tumor cells leading to a decrease in protein synthesis and in cellular proliferation. P70S6K, a serine/threonine kinase, acts downstream of PIP3 and phosphoinositide-dependent kinase-1 in the PI3 kinase pathway, is often upregulated in a variety of cancer cells, and is involved in the regulation of cell growth, proliferation, motility, and survival.Volasertib is a highly potent PLK1 inhibitor with an IC50 of 0.87 nM, as well as the two closely related kinases Plk2 and Plk3 with IC50 values 5 and 56 nM, respectively.

Ginsenoside Rh2, an extract of red Panax ginseng, is a potent anti-inflammatory and anticancer drug.IC50 value:Target:In vitro: Ginsenoside Rh2 inhibited the growth of cultured human UL cells in vitro. Using ELISA, real-time RT-PCR and Western blot methods, we found that Ginsenoside Rh2 significantly reduced the activity of oestrogen receptor alpha (ERα) and c-Src, increased p38 MAPK activity, and reversed ERα activity mediated by PP2 and SB203580, specific inhibitors of c-Src and p38 MAPK, respectively, in UL cells [1]. Ginsenoside Rh2 dose-dependently inhibited the protein, but not messenger RNA (mRNA) of vascular endothelial growth factor A (VEGF-A) in glioblastoma multiforme cells. GRh2 increased the levels of miR-497, which bound to 3′UTR of VEGF-A mRNA to inhibit its translation [2].In vivo: Ginsenoside Rh2 suppressed growth of uterine leiomyomas (ULs) in a rat model and decreased serum hormone levels in a dose-dependent manner [1].

Verbascoside(Acteoside; TJC160), is a bioactive polyphenol from olive oil mill wastewater with known antioxidant activity; protein kinase C inhibitor (IC50 =25 uM).IC50 value:Target:In fresh oocytes, VB exerted prooxidant short-term effects, that is, catalase activity increase and uncoupled increases of mitochondria and reactive oxygen species (ROS) fluorescence signals, and long-term effects, that is, reduced blastocyst formation rate. In vitrified oocytes, VB increased ROS levels. Prooxidant VB effects in ovine prepubertal oocytes could be related to higher VB accumulation, which was found as almost one thousand times higher than that reported in other cell systems in previous studies [1]. Although some "in vitro" genotoxicity of verbascoside has been reported on human lymphocytes with an involvement of PARP-1 and p53 proteins, subsequent "in vivo" tests reported no genotoxicity for high dosage oral administration. It is a protein kinase C inhibitor.

R406 is a competitive Syk inhibitor for ATP binding with a Ki of 30 nM, potently inhibits Syk kinase activity in vitro with an IC50 of 41 nM, measured at an ATP concentration corresponding to its Km value.Sitravatinib is a novel small molecule inhibitor targeting multiple RTKs involved in driving sarcoma cell growth with IC50 of 3980 nmol/Lin vitro: MGCD516 is superior to other multi-kinase inhibitors in inhibiting cell proliferation, RTK phosphorylation, and phosphorylation of downstream effectors. MGCD516 is unique in a way that it has broad spectrum activity against many RTKs including c-Met, c-Kit, Axl, PDGFR, and Eph receptors that are known to play a role in driving sarcoma cell growthIn vivo: MGCD516 induces significant tumor growth suppression than imatinib and crizotinib.

LDK378 2Hcl (Ceritinib) is potent inhibitor against ALK with IC50 of 0.2 nM, shows 40- and 35-fold selectivity against IGF-1R and InsR, respectively. IC50 Value: 0.2 nM [1]Target: ALKin vitro: LDK378 shows great anti-proliferative activity in Ba/F3-NPM-ALK and Karpas290 cells with IC50 of 26.0 nM and 22.8 nM, compared with IC50 of 319.5 nM and 2477 nM in Ba/F3-Tel-InsR and Ba/F3-WT cells [1].in vivo: LDK378 is designed to reduce the possibility of forming reactive metabolites and shows undetectable levels of glutathione (GSH) adducts (<1%) in liver microsomes. LDK378 has relatively good metabolic stability, with moderate CYP3A4 (Midazolam substrate) inhibition and hERG inhibition. LDK378 exhibits low plasma clearance in animals (mouse, rat, dog and monkey) compared to liver blood flow, with the oral bioavailability of above 55% in mouse, rat, dog and monkey. LDK378 induces a dose-dependent growth inhibition and tumor regression in the Karpas299 and H2228 rat xenograft models, with no body-weight loss. LDK378 shows no impact on insulin levels or plasma glucose utilization in the mouse upon chronic dosing up to 100 mg/kg [1].

Centrinone-B is a high affinity and selective PLK4 inhibitor (Ki = 0.59 nM). IC50 value: 0.59 nM (Ki) [1]Target: PLK4in vitro: Centrinone-B is a selective and reversible inhibitor of polo-like kinase 4 (Plk4). Centrinone-B exhibits >2000-fold selectivity for PLK4 over Aurora A and Aurora B.Foretinib is an ATP-competitive inhibitor of HGFR and VEGFR, with IC50 of 0.4 nM and 0.9 nM for Met and KDR, less potent against Ron, Flt-1/3/4, Kit, PDGFRα/β and Tie-2, and has little activity to FGFR1 and EGFR.

E7050(Golvatinib) is a dual c-Met and VEGFR-2 inhibitor with IC50 of 14 nM and 16 nM.IC50 value: 14/16 nM (c-Met/VEGFR2) [1]Target: c-Met/VEGFR2in vitro: In vitro studies indicate that E7050 potently inhibits phosphorylation of both c-Met and VEGFR-2. E7050 also potently represses the growth of both c-met amplified tumor cells and endothelial cells stimulated with either HGF or VEGF [1]. E7050 circumvents resistance to all of the reversible, irreversible, and mutant-selective EGFR-TKIs induced by exogenous and/or endogenous HGF in EGFR mutant lung cancer cell lines, by blocking the Met/Gab1/PI3K/Akt pathway in vitro. E7050 also prevents the emergence of gefitinib-resistant HCC827 cells induced by continuous exposure to HGF [2].in vivo: In vivo studies using E7050 shows inhibition of the phosphorylation of c-Met and VEGFR-2 in tumors, and strong inhibition of tumor growth and tumor angiogenesis in xenograft models. Treatment of some tumor lines containing c-met amplifications with high doses of E7050 (50–200 mg/kg) induces tumor regression and disappearance. In a peritoneal dissemination model, E7050 shows an antitumor effect against peritoneal tumors as well as a significant prolongation of lifespan in treated mice [1]. In another xenograft model research, tumors produced by HGF-transfected Ma-1 (Ma-1/HGF) cells are more angiogenic than vector control tumors and shows resistance to ZD1839. E7050 alone inhibits angiogenesis and retards growth of Ma-1/HGF tumors. E7050 combined with ZD1839 induces marked regression of tumor growth [3].

FIIN-2 is an irreversible inhibitor of FGFR1-4 with IC50 values of 3.1, 4.3, 27, and 45 nM, respectively. IC50 value: 3.1, 4.3, 27, and 45 nM [1]Target: FGFR1-4in vitro: FIIN-2 also moderately inhibits EGFR, with an IC50 of 204 nM. The Cys491 of FGFR2 is the primary labeled site for FIIN-2 binding. FIIN-2 is the first class of inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2. The co-crystal structure of FGFR4 with FIIN-2 was reported, which unexpectedly exhibits a "DFG-out" covalent binding mode. FIIN-2 maintains the pyrimido[4,5-d] pyrimidinone core of FIIN-1 but removes the two chlorine atoms, which are crucial for FIIN-1's potency against FGFR. FIIN-2 maintains the ability to form a covalent bond with the P-loop cysteine but alter the selectivity profile versus other kinases. Compared with FIIN-1, FIIN-2 displays strong binding to FGFRs and exhibited good overall kinase selectivity. FIIN-2 exhibits much less affinity for EGFR, but FIIN-3 potently bound to WT EGFR and to a subset of EGFR mutants. FIIN-2 inhibits proliferation of FGFR1-4 Ba/F3 cells with EC50s in the nanomolar range and were especially potent against FGFR2, with EC50s in the 1-nM range. FIIN-2 also inhibited the FGFR2 V564M gatekeeper mutant Ba/F3 cells, with EC50s of 58 nM, whereas FIIN-1 and BGJ398 had EC50s of over 1.0 μM against this mutant. FIIN-2 showed good potency against gatekeeper mutant V564F. In contrast, FIIN-2 was fourfold less potent (EC50 of 506 nM). FIIN-2 was inactive up to a concentration of 1.8 μM against EGFR L858R. FIIN-2 showed rather poor potency against protein kinase FLT1 (FLT1). In WT FGFR2 Ba/F3 cells, FIIN-2 completely inhibits the FGFR2 autophosphorylation on mutations of Tyr656/657 and V564M at concentrations of 3 nM and 300 nM, respectively. [1]

CEP-28122 mesylate salt is a highly potent and selective orally active ALK inhibitor with IC50 of 1.9 ± 0.5 nM in an enzyme-based TRF assay.IC50 value: 1.9 ± 0.5 nMTarget: ALKin vitro: CEP-28122 is a potent inhibitor of recombinant ALK activity and cellular ALK tyrosine phosphorylation. CEP-28122 also inhibits Flt4 with IC50 of 46 ±10 nM. CEP-28122 induces concentration-dependent growth inhibition/cytotoxicity of ALK-positive anaplastic large-cell lymphoma (ALCL), non-small celllung cancer (NSCLC), and neuroblastoma cells. [1]in vivo: CEP-28122 displays dose-dependent inhibition of ALK tyrosine phosphorylation in tumor xenografts in mice, with substantial target inhibition (>90%) for more than12 hours following single oral dosing at 30 mg/kg. Dose-dependent antitumor activity was observed in ALK-positive ALCL, NSCLC, and neuroblastoma tumor xenografts in mice administered CEP-28122 orally, with complete/near complete tumor regressions observed following treatment at doses of 30 mg/kg twice daily or higher. [1]

Cabozantinib (S-malate) is a potent VEGFR2 inhibitor with IC50 of 0.035 nM, and also inhibits c-Met, Ret, Kit, Flt-1/3/4, Tie2, and AXL with IC50s of 1.3 nM, 4 nM, 4.6 nM, 12 nM/11.3 nM/6 nM, 14.3 nM and 7 nM, respectively.CO-1686 hydrobromide is an orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR including T790M, and the IC50 values for EGFRL858R/T790M and EGFRWT are 21.5 nM and 303.3 nM, respectively.PHA-665752 is a potent, selective and ATP-competitive c-Met inhibitor with IC50 of 9 nM, >50-fold selectivity for c-Met than RTKs or STKs.IC50 value: 9 nMTarget: c-Metin vitro: PHA-665752 significantly inhibits c-Met kinase activity with Ki of 4 nM, and exhibits >50-fold selectivity for c-Met compared with various tyrosine and serine-threonine kinases. PHA-665752 potently inhibits the HGF-stimulated c-Met autophosphorylation with IC50 of 25-50 nM. PHA-665752 also significantly blocks HGF- and c-Met-dependent functions such as cell motility and cell proliferation with IC50 of 40-50 nM and 18-42 nM, respectively. In addition, PHA-665752 potently inhibits HGF-stimulated or constitutive phosphorylation of mediators of downstream of c-Met such as Gab-1, ERK, Akt, STAT3, PLC-γ, and FAK in multiple tumor cell lines [1]. PHA-665752 inhibits cell growth in TPR-MET-transformed BaF3 cells with IC50 of <60 nM, and inhibits constitutive cell motility and migration by 92.5% at 0.2 μM. Inhibition of c-Met by PHA665752 (0.2 μM) also induces cell apoptosis of 33.1% and G1 cell cycle arrest with cells in G1 phase increasing from 42.4% to 77.0%. PHA665752 can cooperate with rapamycin to inhibit cell growth of TPR-MET-transformed BaF3 cells and non-small cell lung cancer H441 cells [2].in vivo: Administration of PHA-665752 induces a dose-dependent tumor growth inhibition of S114 xenografts by 20 %, 39% and 68%, at dose of 7.5, 15, and 30 mg/kg/day, respectively [1]. PHA665752 treatment significantly reduces the tumor growth of NCI-H69, NCI-H441 and A549 in mouse xenografts by 99%, 75%, and 59%, respectively. PHA665752 also significantly inhibits angiogenesis by >85%, due to decreasing the production of vascular endothelial growth factor and increasing the production of the angiogenesis inhibitor thrombospondin-1 [3].

NVP-BEZ235 is a dual PI3K and mTOR kinase inhibitor with IC50 values of 4, 75, 7, 5 nM for PI3Kα, β, γ, δ, respectively.

Nintedanib esylate (BIBF 1120 esylate) is a potent triple angiokinase inhibitor for VEGFR1/2/3, FGFR1/2/3 and PDGFRα/β with IC50 of 34 nM/13 nM/13 nM, 69 nM/37 nM/108 nM and 59 nM/65 nM. IC50 value: Target: VEGFR/FGFR/PDGFRin vitro: BIBF1120 inhibits PDGFR kinase activity of PDGFR alpha and PDGFR beta types with IC50 values of 59 nM and 65 nM, respectively. In addition, BIBF1120 suppresses the FGFR subtypes with IC50 of 60 nM, 37 nM and 108 nM for FGFR1, FGFR2, and FGFR3, respectively. BIBF1120 binds to the ATP-binding site in the cleft between the amino and carboxy terminal lobes of the kinase domain. The indolinone scaffold forms two hydrogen bonds with the backbone nitrogen of Cys919 and the backbone carbonyl oxygen of Glu917 in the hinge region. BIBF 1120 inhibits proliferation of PDGF-BB stimulated BRPs with EC50 of 79 nM in cell assays. BIBF1120 at concentrations as low as 100 nM blocks activation of MAPK after stimulation with 5% serum plus PDGF-BB. In cultures of human vascular smooth muscle cells (HUASMC), BIBF1120 prevents PDGF-BB stimulated proliferation with an EC50 of 69 nM. in vivo: In all tumor models tested thus far, including human tumor xenografts growing in nude mice and a syngeneic rat tumor model, BIBF1120 is highly active at well-tolerated doses (25-100 mg/kg daily p.o.). This is evident in the magnetic resonance imaging of tumor perfusion after 3 days, reducing vessel density and vessel integrity after 5 days, and profound growth inhibition.

NVP-BGT226(BGT 226) is a novel class I PI3K/mTOR inhibitor for PI3Kα/β/γ with IC50 of 4 nM/63 nM/38 nM.IC50 value: 4 nM/63 nM/38 nM(PI3Kα/β/γ) [1]Target: PI3Kin vitro: The anti-proliferative and pro-apoptotic effects of NVP-BGT226 are independent of bcr-abl status. The activation of the AKT/mTOR signal cascade is suppressed by NVP-BGT226 in a concentration- and time-dependent manner. Flow cytometric analysis exhibits an accumulation of cells in the G(0)-G(1) phase with concomitant loss in the S-phase. NVP-BGT226 displays potent growth-inhibitory activity against all tested cell lines including SCC4, TU183 and KB cell lines with the IC50 ranging from 7.4 to 30.1 nM. Notably, both Detroit 562 and HONE-1 cells, which express PIK3CA mutation H1047R, are still sensitive to the growth-inhibitory effect of NVP-BGT226 treatment. In addition, the sensitivity to NVP-BGT226 between HONE-1 cells and its cisplatin-resistant variant is almost identical. Results of the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and the analysis of caspase 3/7 and PARP indicates that NVP-BGT226 induces cancer cell death through an apoptosis-independent pathway. NVP-BGT226 induces autophagy as indicated by the aggregation and upregulation of the microtubule-associated protein light chain 3B-II, and p62 degradation. Gene silencing of Beclin1 or cotreatment of the autophagosome inhibitor, 3-methyladenine, inhibits the NVP-BGT226-induced autophagy and leads to the retrieval of colony survival [2]. NVP-BGT226 inhibits growth in common myeloma cell lines and primary myeloma cells (such as NCI-H929, U266, RPMI-8226 and OPM2 MM cell lines) at nanomolar concentrations in a time-dependent and dose-dependent manner. NVP-BGT226 inhibits phosphorylation of protein kinase B (Akt), P70S6k and 4E-BP-1 in a time-dependent and dose-dependent manner [3].in vivo: In a xenografted animal model, NVP-BGT226 significantly delays tumor growth in a dose-dependent manner, along with suppressed cytoplasmic expression of p-p70 S6 kinase and the presence of autophagosome formation. NVP-BGT226 inhibits tumor growth in a dose-dependent manner in a FaDu cell xenografted mouse model. Oral administration of NVP-BGT226 at 2.5 and 5 mg/kg for 3 weeks causes 34.7% and 76.1% reduction of the tumor growth on day 21, respectively (compared with control). NVP-BGT226 displays comparable inhibition against tumor growth to rapamycin. The final volume of both groups is significantly smaller than those treated with LY294002 (a PI3K inhibitor) or the control [2].

Flumatinib mesylate (HH-GV-678 mesylate), a derivative of imatinib, is a multi-kinase inhibitor with IC50 Values of 1.2 nM, 307.6 nM and 2662 nM for c-Abl, PDGFRβ and c-Kit respectively.IC50 Value: 1.2 nM (c-Abl); 307.6 nM(PDGFRβ); 2662 nM (c-Kit) [1]Target: c-Abl; c-Kit; PDGRFβin vitro: HH-GV-678 can predominantly inhibit the autophosphorylation of Bcr-Abl in K562 cell. In higher concentration, HH-GV-678 can inhibit the phosphorylation of c-Kit in Mo7e cell and the phosphorylation of PDGFR in Swiss3T3 cell, however, HH-GV-678 has no or little effect on other tyrosine kinase including EGFR/KDR/c-Src andHER2 [1]. Flumatinib effectively overcame the drug resistance of certain KIT mutants with activation loop mutations (i.e., D820G, N822K, Y823D, and A829P) [2].in vivo: The purpose of this study was to identify the metabolites of flumatinib in CML patients, with the aim of determining the main metabolic pathways offlumatinib in humans after oral administration. Ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry revealed 34 metabolites; 7 primary metabolites were confirmed by comparison with synthetic reference standards. The results show that the parent drugflumatinib was the main form recovered in human plasma, urine, and feces. The main metabolites of flumatinib in humans were the products of N-demethylation, N-oxidation, hydroxylation, and amide hydrolysis [3].

PF-562271 (besylate) is a potent, ATP-competitive, reversible inhibitor of FAK and Pyk2 kinase with IC50 of 1.5 nM and 13 nM, and has > 100-fold selectivity against other protein kinases, except for some CDKs.

Icariin(Ieariline) is a major constituent of flavonoids from the Chinese medicinal herb Epimedium brevicornum; exhibits multiple biological properties, including anti-inflammatory, neuroregulatory and neuroprotective activities. IC50 value:Target: in vitro: Icariin significantly protected pulmonary function and attenuated CS-induced inflammatory response by decreasing inflammatory cells and production of TNF-α, IL-8 and MMP-9 in both the serum and BALF of CS-exposed mice and decreasing production of TNF-α and IL-8 in the supernatant of CSE-exposed A549 cells [1]. 4 μM or 20 μM Icariin treatment significantly inhibited the cholesterol ester (CE)/total cholesterol (TC) and oxLDL-mediated foam cell formation (P < 0.05). The binding of oxLDL to LPS-activated macrophages was also significantly hindered by Icariin (P < 0.05). Furthermore, Icariin down-regulated the expression of CD36 in LPS-activated macrophages in a dose-dependent manner and CD36 over-expression restored the inhibitory effect of Icariin on foam cell formation [2]. in vivo: icariin treatment leads to alleviated inflammatory infiltration and reduced blood-brain barrier leakage (BBB) of the paracellular tracer (FITC-dextran) in EAE. Mice that received icariin-treated T cells also displayed lower EAE scores and better clinical recovery from EAE. Icariin administration suppresses the frequencies of Th1 and Th17 cells in the splenocytes and lymph node cells. Icariin-treated mice also show lower frequency of Th17 cells in CNS mononuclear cells [3]. Icariin was suspended in carboxymethylcellulose and given orally to APP/PS1 mice. Following an oral treatment of 10 days, Icariin significantly attenuated Aβ deposition, microglial activation and TGF-β1 immunoreactivity at amyloid plaques in cortex and hippocampus of transgenic mice 5 months of age, and restored impaired nesting ability [4].

Trametinib DMSO solvate is a potent MEK1/2 inhibitor that specifically inhibits MEK1/2, with an IC50 value of about 2 nM.c-Met inhibitor 2 is a potent compound that has activity against cancers dependent upon Met activation and also has activity against cancers as a VEGFR inhibitor. IC50 value:Target: c-Met, VEGFRMore details please refer to Patent WO 2009094417 A1.

GDC-0941 2 MeSO3H salt is a potent inhibitor of PI3Kα/δ with IC50 of 3 nM, with modest selectivity against p110β (11-fold) and p110γ (25-fold).IC50 value: 3 nMTarget: PI3Kα/δGDC-0941 is a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. GDC-0941 against p110a IC50=0.003μM,U87MG IC50=0.95μM, A2780 IC50=0.14 μM, and in vitro metabolic stability in mouse and human is 91.96%. The inhibitions of U87MG , PC3, MDA-MB-361 cancer cell proliferation are (IC50) 0.95, 0.28, 0.72 μM, respectively.Afatinib dimaleate is an irreversible, dual EGFR/HER2 inhibitor, shows potent activity against wild-type and mutant forms of EGFR and HER2, with IC50 of 0.5 nM, 0.4 nM, 10 nM and 14 nM for EGFRwt, EGFRL858R, EGFRL858R/T790M and HER2, respectively.

KN-62 is a selective and potent inhibitor of calmodulin-dependent protein kinase II (CaMK-II) with IC50 of 0.9 μM, KN-62 also displays noncompetitive antagonism at P2X7 receptors in HEK293 cells, with an IC50 value of approximately 15 nM.R788 sodium salt hydrate (Fostamatinib), a prodrug of the active metabolite R406, is a potent Syk inhibitor with IC50 of 41 nM.IC50 Value: 41 nM [1]Target: Sykin vitro: R788 is a methylene phosphate prodrug of R406, which can be rapidly converted to R406 in vivo. R406 (in vitro active form of R788) selectively inhibits Syk-dependent signaling with EC50 values ranging from 33 nM to 171 nM, more potently than Syk-independent pathways in different cells [1]. R406 inhibits cellular proliferation of a variety of diffuse large B-cell lymphoma (DLBCL) cell lines with EC50 values ranging from 0.8 μM to 8.1 μM [2]. R406 treatment reduces basal phosphorylation of BLNK, Akt, glycogen synthase kinase-3 (GSK-3), forkhead box O (FOXO) and ERK not only in cells with high (TCL-002) but also in cells with low levels of phosphorylated Syk (TCL1-551). In addition, R406 completely inhibits the anti-IgM induced Bcr signal in TCL1 leukemias. Despite the higher levels of constitutively active Syk in TCL1 leukemias, R406 is not selectively cytotoxic to the leukemic cells [3]. in vivo: R788 effectively inhibits BCR signaling in vivo, resulting in reduced proliferation and survival of the malignant B cells and significantly prolonged survival of the treated animals [3].

Astragaloside IV, an active component isolated from Astragalus membranaceus, suppresses the activation of ERK1/2 and JNK, and downregulates matrix metalloproteases (MMP)-2, (MMP)-9 in MDA-MB-231 breast cancer cells.

GSK1904529A is a selective inhibitor of IGF-1R and IR with IC50 of 27 nM and 25 nM, >100-fold more selective for IGF-1R/InsR than Akt1/2, Aurora A/B,B-Raf, CDK2, EGFR etc. IC50 value: 27/25 nM (IGF1R/IR) [1]Target: IGF1R/IRin vitro: GSK1904529A is a reversible, ATP-competitive inhibitor and has enzyme-inhibitor binding values against IGF-1R and IR with Ki of 1.6 nM and 1.3 nM, respectively. GSK1904529A potently inhibits the ligand-induced phosphorylation of IGF-1R and IR at concentrations above 0.01 μM, followed by blocking downstream signaling (AKT, IRS-1, and ERK). GSK1904529A potently inhibits NIH-3T3/LISN, TC-71, SK-N-MC, SK-ES RD-ES cells with IC50 of 60 nM, 35 nM, 43 nM, 61 nM and 62 nM, respectively. GSK1904529A also inhibits other multiple myeloma and Ewing's sarcoma cell lines including NCI-H929, MOLP-8, LP-1 and KMS-12-BM etc. GSK1904529A induces cell cycle arrest at the G1 phase in cell lines COLO 205, MCF-7, and NCI-H929, which are sensitive to GK1904529A [1].in vivo: GSK1904529A indicates 98% tumor growth inhibition in NIH-3T3/LISN tumor-bearing mice at a dose of 30 mg/kg (orally, twice-daily) and 75% in COLO 205 xenografts mice (once daily). Among HT29 and BxPC3 xenografts, GSK1904529A produces moderate tumor growth inhibition with no side effects at a dose of 30 mg/kg. Meanwhile, GSK1904529A shows minimal effects on blood glucose levels. GSK1904529A (~3.5 μM in blood) completely inhibits IGF-1R phosphorylation. GSK1904529A has been implicated in treatment of various IGF-1R-dependent tumors including prostate, colon, breast, pancreatic, ovarian, and sarcomas [1].

Lapatinib ditosylate is a potent EGFR and ErbB2 inhibitor with IC50 of 10.2 and 9.8 nM, respectively.

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