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Functional characterization of an isoform-selective inhibitor of PI3K p110β as a potential anti-cancer agent Ni et al, Supplementary data Supplementary Methods Pharmacokinetic evaluation of KIN-193. This analysis was performed at the Sai Advantium Pharma Limited Company (India) with 3 groups of 9 male Swiss Albino mice. Animals in Group 1 were dosed via the tail vein at 1 mg/kg of KIN- 193 solution (7.5% v/v N-methyl pyrrolidone and 40% v/v polyethylene glycol-400 in normal saline). Group 2 animals were dosed orally at 10 mg/kg with a suspension formulation (0.5% w/v Na CMC with 0.1% v/v Tween-80 in water) of KIN193. Group 3 animals were dosed intraperitoneally at 10 mg/kg with a formulation of KIN-193 in 10% v/v ethanol and 20% v/v PEG-400 in water. Blood samples were collected at 0, 0.08 (for iv and ip only), 0.25, 0.5, 1, 2, 4, 6, (for oral and ip only) 8, 12 and 24 hours (for iv, oral and ip). The blood samples were collected from sets of three mice at each time point in tubes containing K2EDTA as an anticoagulant. Plasma samples were separated by centrifugation and stored below -70°C until bioanalysis. All samples were processed by precipitation using acetonitrile and analyzed with a LC-MS/MS method (LLOQ - 1.138 ng/mL). Pharmacokinetic parameters were calculated using the non-compartmental analysis tool of WinNonlin® Enterprise software (version 5.2). Supplementary Figure legends: Figure S1. Establishment of a cell-based system for PI3K isoform-specific inhibitor screening. HMEC cells stably expressing myristoylated-HA-tagged p110α (myr-p110α, termed CA-p110α), myr-p110β (CA-p110β) or myr-p110δ (CA-p110δ) individually were serum-starved for 2 hours,

Transcript of Functional characterization of an isoform-selective ... · Functional characterization of an...

Page 1: Functional characterization of an isoform-selective ... · Functional characterization of an isoform-selective inhibitor of PI3K p110β as a potential anti-cancer agent Ni et al,

Functional characterization of an isoform-selective inhibitor of PI3K

p110β as a potential anti-cancer agent

Ni et al, Supplementary data

Supplementary Methods

Pharmacokinetic evaluation of KIN-193.

This analysis was performed at the Sai Advantium Pharma Limited Company (India) with 3 groups

of 9 male Swiss Albino mice. Animals in Group 1 were dosed via the tail vein at 1 mg/kg of KIN-

193 solution (7.5% v/v N-methyl pyrrolidone and 40% v/v polyethylene glycol-400 in normal

saline). Group 2 animals were dosed orally at 10 mg/kg with a suspension formulation (0.5% w/v Na

CMC with 0.1% v/v Tween-80 in water) of KIN193. Group 3 animals were dosed intraperitoneally

at 10 mg/kg with a formulation of KIN-193 in 10% v/v ethanol and 20% v/v PEG-400 in water.

Blood samples were collected at 0, 0.08 (for iv and ip only), 0.25, 0.5, 1, 2, 4, 6, (for oral and ip

only) 8, 12 and 24 hours (for iv, oral and ip). The blood samples were collected from sets of three

mice at each time point in tubes containing K2EDTA as an anticoagulant. Plasma samples were

separated by centrifugation and stored below -70°C until bioanalysis. All samples were processed by

precipitation using acetonitrile and analyzed with a LC-MS/MS method (LLOQ - 1.138 ng/mL).

Pharmacokinetic parameters were calculated using the non-compartmental analysis tool of

WinNonlin® Enterprise software (version 5.2).

Supplementary Figure legends:

Figure S1. Establishment of a cell-based system for PI3K isoform-specific inhibitor screening.

HMEC cells stably expressing myristoylated-HA-tagged p110α (myr-p110α, termed CA-p110α),

myr-p110β (CA-p110β) or myr-p110δ (CA-p110δ) individually were serum-starved for 2 hours,

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then treated with PIK-75 (p110α inhibitor), TGX-221 (β inhibitor), IC87751 (δ inhibitor) or GDC-

0941 (pan inhibitor) at the indicated doses for 1h. Cell lysates were prepared and subjected to

western blot assays with the indicated antibodies.

Figure S2. Identification of KIN-193 as a p110β specific inhibitor. A, Schematic flow chart of

Lanthascreen cellular assay of plate-based fluorescence-screening for testing of compounds’

inhibition of AKT phosphorylation at both T308 and S473 in HMEC cell lines expressing CA-

p110α, CA-p110β or CA-p110δ. B, IC50 values for selected small molecule inhibitors against various

PI3K p110 isoforms in isogenic HMEC lines expressing CA-p110α, CA-p110β, or CA-p110δ using

Lanthascreen assays.

Figure S3. HMEC cell lines stably expressing CA-p110α, CA-p110β or CA-p110δ were serum-

starved for 2 hours, then treated with TGX-221 or KIN-193 at the indicated doses for 1h. Cell lysates

were prepared and subjected to western blot assays with the indicated antibodies.

Figure S4. Western blot analyses of PTEN and PI3K protein expression in the indicated cell lines.

Figure S5. Pharmacokinetics of KIN-193 in mice. A, Plasma concentrations of KIN-193 following

a single administration IV (1 mg/kg), PO (10 mg/kg), or ip (10 mg/kg) to male Swiss albino mice.

Plasma samples were analyzed for KIN-193 by LC-MS/MS methods. B, Nude mice bearing ~500

mm3 Rat-CA-p110α/β xenografts were given a single ip administration of KIN-193 (10 mg/kg).

Plasma samples were collected at 0, 1, 4, 8, and 24 h following compound administration and

analyzed for KIN-193 by LC-MS/MS methods.

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Supplementary Table Titles

Table S1. Chemical structures of the compounds collected for PI3K isoform-specific cellular assays.

Table S2. KinomeScanTM profiling of KIN-193 against 433 kinases.

Table S3. IC50 values for KIN-193 in 422 cancer cell lines. The PTEN status is given for each cell

line.

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Ni et al Supplementary Figure. 1

CA

-p11

0α c

ells

DM

SO

cont

rol c

ells

PIK-75

0.05 0.1

TGX-221 IC87114

0.01 0.1 0.5 0.01 0.1 0.5 0.01

GDC-0941

0.1 0.5 0.01

pAktS473

pAktT308

Akt

α-tubulin

pAktS473

pAktT308

Akt

α-tubulin

pAktS473

pAktT308

Akt

α-tubulin CA

-p11

0β c

ells

C

A-p

110δ

cel

ls

p110 inhibitor α β δ pan

Dose (µM)

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(Serum free)

add inhibitor BacMamGFP-Akt

HMEC- CA-p110α CA-p110β CA-p110δ

overnight overnight

plate cells Lyse cells in

presence of Tb-pAkt-Ab

1h

detection

2h

LS-pAkt308 (HMEC-CAp110b-BacAkt)

-4 -2 0 20

2

4

6

8

10

[TGX-221] (uM)

Re

spn

ose

Ra

tio

IC50

TGX-221

0.02487IC50= 0.025 µM Response ratio: 8.3 Z’ factor: 0.78

log[TGX-221] (µM)

A

B

Ni et al Supplementary Figure. 2

CAp110α-pAktT308

CAp110α-pAktS473

CAp110β-pAktT308

CAp110β-pAktS473

CAp110δ-pAktT308

CAp110δ-pAktS473

KIN-150 0.2038 0.0135 2.1155 0.0217 0.3544 0.0210

KIN-151 0.0253 0.0393 0.1769 0.2342 0.1796 0.1574

KIN-152 0.0183 0.0254 0.2861 0.2629 0.0109 0.0119

KIN-167 0.0136 0.0092 0.0068 0.0059 0.0007 0.0003

KIN-169 > 5 > 5 0.0169 0.0206 0.2471 0.3101

KIN-170 0.4256 0.3122 0.4957 0.5554 0.3339 0.2067

KIN-171 0.0206 0.0121 0.0111 0.0096 0.0104 0.0086

KIN-172 0.0801 0.0585 0.0948 0.0797 0.0689 0.0581

KIN-173 0.2872 0.3081 1.6980 2.5220 1.1210 0.8935

KIN-174 0.7453 0.8733 1.9150 2.0270 0.3356 0.5583

KIN-193 > 5 > 5 0.0117 0.0224 0.8206 0.9566

KIN-194 > 5 > 5 > 5 > 5 0.4959 0.8307

KIN-195 0.5918 0.9826 > 5 > 5 0.2490 0.2523

KIN-196 > 5 > 5 1.2462 1.7370 0.0078 0.0213

KIN-197 0.0146 0.0160 0.0289 0.0332 0.0066 0.0081

KIN-203 0.0076 0.0119 0.2952 0.1601 0.0033 0.0052

KIN-266 0.0280 0.0033 0.5455 0.0029 0.1032 0.0075

KIN-267 0.0616 0.0820 0.2239 0.2064 0.0242 0.0308

KIN-268 0.1213 0.0322 0.7398 0.0327 0.1500 0.0553

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DM

SO

Con

trol c

ells

pAktS473

pAktT308

Akt

CA

-p11

0α c

ells

α-tubulin

TGX-221

0.1 1 0.01 Dose (µM)

KIN-193

0.1 1 0.01 C

A-p

110β

cel

ls

pAktS473

pAktT308

Akt

α-tubulin

Ni et al Supplementary Figure. 3

CA

-p11

0δ c

ells

pAktS473

pAktT308

Akt

α-tubulin

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p85

vinculin

p110α

p110β

PTEN

Ni et al Supplementary Figure. 4

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Route Cmax (ng/mL) Tmax (h) AUCINF

(hr*ng/mL) T1/2 (hr) Cl (mL/min/Kg) Vss (L/Kg) F (%)

IV(1mg) 780 - 112 2.75 148 10.3 - PO(10mg) 74.1 0.25 101 - - - 6.85 I.P.(10mg) 2074 0.08 1140 1.1 - - -

A

B

[KIN

-193

] (µM

)

Time (hr)

blood

0h 1h 4h 8h 24h

0

2

4

6

[KIN-193]

Ni et al Supplementary Figure. 5

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Supplementary table 1

KIN150 BEZ235 CC(C)(C#N)C1=CC=C(C=C1)N2C3=C4C=C(C=CC4=NC=C3N(C2=O)C)C5=CC6=CC=CC=C6N=C5

Chemistry 1 Mol Cancer Ther. 2008 Jul;7(7):1851-63. Epub 2008 Jul 7.Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity.Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, Brachmann S, Chène P, De Pover A, Schoemaker K, Fabbro D, Gabriel D, Simonen M, Murphy L, Finan P, Sellers W, García-Echeverría C.

KIN151 CN(S(=O)(C1=CC([N+]([O-])=O)=CC=C1C)=O)/[N]([H])=C/C2=CN=C3N2C=C(Br)C=C3.[Cl]

Chemistry 2 Bioorg Med Chem. 2007 Sep 1;15(17):5837-44. Epub 2007 Jun 6.Synthesis and biological evaluation of sulfonylhydrazone-substituted imidazo[1,2-a]pyridines as novel PI3 kinase p110alpha inhibitors.Hayakawa M, Kawaguchi K, Kaizawa H, Koizumi T, Ohishi T, Yamano M, Okada M, Ohta M, Tsukamoto S, Raynaud FI, Parker P, Workman P, Waterfield MD.

KIN152 O=C(C1=CC=CN=C1)NC2=NC3=C(OC)C(OC)=CC=C3C4=NCCN24

Chemistry 3 Cancer Cell. 2006 May;9(5):341-9.A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma.Fan QW, Knight ZA, Goldenberg DD, Yu W, Mostov KE, Stokoe D, Shokat KM, Weiss WA.

KIN167

ZSTK474

FC(F)C1=NC2=C(C=CC=C2)N1C3=NC(N4CCOCC4)=NC(N5CCOCC5)=N3

Chemistry 4 J Natl Cancer Inst. 2006 Apr 19;98(8):545-56.Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor.Yaguchi S, Fukui Y, Koshimizu I, Yoshimi H, Matsuno T, Gouda H, Hirono S, Yamazaki K, Yamori T.

KIN169 TGX-221 CC(C=C1C(C)NC2=CC=CC=C2)=CN3C1=NC(N4CCOCC4)=CC3=O

Chemistry 5 Nat Med. 2005 May;11(5):507-14. Epub 2005 Apr 17.PI 3-kinase p110beta: a new target for antithrombotic therapy.Jackson SP, Schoenwaelder SM, Goncalves I, Nesbitt WS, Yap CL, Wright CE, Kenche V, Anderson KE, Dopheide SM, Yuan Y, Sturgeon SA, Prabaharan H, Thompson PE, Smith GD, Shepherd PR, Daniele N, Kulkarni S, Abbott B, Saylik D, Jones C, Lu L, Giuliano S, Hughan SC, Angus JA, Robertson AD, Salem HH.

KIN170 O=C(C1=CC=C(N)N=C1)NC2=CC(C3=NC4=C(OC5=C4C=CC=N5)C(N6CCOCC6)=N3)=CC=C2

Chemistry 6 EMBO Rep. 2008 Feb;9(2):164-70. Epub 2008 Jan 11.A selective PIKfyve inhibitor blocks PtdIns(3,5)P(2) production and disrupts endomembrane transport and retroviral budding.Jefferies HB, Cooke FT, Jat P, Boucheron C, Koizumi T, Hayakawa M, Kaizawa H, Ohishi T, Workman P, Waterfield MD, Parker PJ.

KIN171 PI103 OC1=CC(C2=NC3=C(OC4=C3C=CC=N4)C(N5CCOCC5)=N2)=CC=C1

Chemistry 7 Cancer Cell. 2006 May;9(5):341-9.A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma.Fan QW, Knight ZA, Goldenberg DD, Yu W, Mostov KE, Stokoe D, Shokat KM, Weiss WA.SourceKnight, Z. A. et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 125, 733-747 (2006).

KIN172 OC1=CC(C2=NC3=C(SC=C3)C(N4CCOCC4)=N2)=CC=C1

Chemistry 8 Bioorg Med Chem. 2006 Oct 15;14(20):6847-58. Epub 2006 Jul 11.Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110alpha inhibitors.Hayakawa M, Kaizawa H, Moritomo H, Koizumi T, Ohishi T, Okada M, Ohta M, Tsukamoto S, Parker P, Workman P, Waterfield M.

KIN173 AS-605240 [H]/C(C1=CC2=NC=CN=C2C=C1)=C3C(NC(S/3)=O)=O

Chemistry 9 Nat Med. 2005 Sep;11(9):936-43. Epub 2005 Aug 28.Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis.Camps M, Rückle T, Ji H, Ardissone V, Rintelen F, Shaw J, Ferrandi C, Chabert C, Gillieron C, Françon B, Martin T, Gretener D, Perrin D, Leroy D, Vitte PA, Hirsch E, Wymann MP, Cirillo R, Schwarz MK, Rommel C.

KIN174

AS 252424

[H]/C(C1=CC=C(C2=CC=C(F)C=C2O)O1)=C3C(NC(S/3)=O)=O

Chemistry 10 J Med Chem. 2006 Jun 29;49(13):3857-71.Furan-2-ylmethylene thiazolidinediones as novel, potent, and selective inhibitors of phosphoinositide 3-kinase gamma.Pomel V, Klicic J, Covini D, Church DD, Shaw JP, Roulin K, Burgat-Charvillon F, Valognes D, Camps M, Chabert C, Gillieron C, Françon B, Perrin D, Leroy D, Gretener D, Nichols A, Vitte PA, Carboni S, Rommel C, Schwarz MK, Rückle T.

KIN193 CC(C=C1[C@@H](C)NC2=CC=CC=C2C(O)=O)=CN3C1=NC(N4CCOCC4)=CC3=O

Chemistry 11 Preparation of enantiomerically pure (-)2-[1-(7-Me-2-(morpholin-4-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethylamino]benzoic acid, its use as a selective PI 3-kinase β inhibitor for therapyBy Fjellstroem, Ola; Gustafsson, David; Jackson, Shaun; Lundberg, Jan AaFrom PCT Int. Appl. (2009), WO 2009093972 A1 20090730. Language: English, Database: CAPLUS

KIN194 IC87114 O=C1N(C2=CC=CC=C2OC)C(CSC3=NC=NC4=C3N=CN4)=NC5=C1C(Cl)=CC=C5

Chemistry 12 Eur J Med Chem. 2006 Apr;41(4):558-65. Epub 2006 Mar 20.Action mechanisms and structure-activity relationships of PI3Kgamma inhibitors on the enzyme: a molecular modeling study.Kuang RR, Qian F, Li Z, Wei DZ, Tang Y.

KIN195 O=C(N(C)C)CNC(NC1=NC(C)=C(C2=CC=C(S(=O)(C)=O)C(F)=C2)S1)=O

Chemistry 13 Preparation of phenylthiazolylureas as inhibitors of phosphatidylinositol 3-kinaseBy Bloomfield, Graham Charles; Bruce, Ian; Hayler, Judy Fox; Leblanc, Catherine; Le Grand, Darren Mark; McCarthy, CliveFrom PCT Int. Appl. (2005), WO 2005021519 A2 20050310. Language: English, Database: CAPLUS

KIN196 PIK294 O=C1N(C2=CC=CC=C2C)C(CN3N=C(C4=CC=CC(O)=C4)C5=C(N)N=CN=C53)=NC6=C1C(C)=CC=C6

Chemistry 14 Cell. 2006 May 19;125(4):733-47. Epub 2006 Apr 27.A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling.Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, Loewith R, Stokoe D, Balla A, Toth B, Balla T, Weiss WA, Williams RL, Shokat KM.

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KIN197 CC(N=C(N)N=C1)=C1C2=NC3=C(SC(CN4CCN(S(=O)(C)=O)CC4)=C3)C(N5CCOCC5)=N2

Chemistry 15 J Med Chem. 2010 Feb 11;53(3):1086-97.Discovery of (thienopyrimidin-2-yl)aminopyrimidines as potent, selective, and orally available pan-PI3-kinase and dual pan-PI3-kinase/mTOR inhibitors for the treatment of cancer.Sutherlin DP, Sampath D, Berry M, Castanedo G, Chang Z, Chuckowree I, Dotson J, Folkes A, Friedman L, Goldsmith R, Heffron T, Lee L, Lesnick J, Lewis C, Mathieu S, Nonomiya J, Olivero A, Pang J, Prior WW, Salphati L, Sideris S, Tian Q, Tsui V, Wan NC, Wang S, Wiesmann C, Wong S, Zhu BY.

KIN203 COC1=C(N=C(NC(C2=CN=C(N)C=C2)=O)N3C4=NCC3)C4=CC=C1OCCCS(=O)(N5CCOCC5)=O

Chemistry 16 Preparation of sulfonyldihydroimidazoquinazoline derivatives for use as PIK3 inhibitorsBy Henteman, Martin F.; Scott, William; Wood, Jill; Johnson, Jeffrey; Redman, Aniko; Bullion, Ann-Marie; Guernon, LeatteFrom PCT Int. Appl. (2009), WO 2009091550 A2 20090723. Language: English, Database: CAPLUS

KIN266 torin2 C1(C(C=CC2N)=CN=2)=CC(=C2C=C1)C(=C1C=N2)N(C(C=CC2)=CC=2C(F)(F)F)C(C=C1)=O

Chemistry 17 J Med Chem. 2011 Mar 10;54(5):1473-80. Epub 2011 Feb 15.Discovery of 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer.Liu Q, Wang J, Kang SA, Thoreen CC, Hur W, Ahmed T, Sabatini DM, Gray NS.

KIN267 GDC-0941 O1CCN(CC1)C(=N1)C2SC(=CC=2N=C1C(C=CC1)=C(C=N2)C=1N2)CN1CCN(CC1)S(C)(=O)=O

Chemistry 18 J Med Chem. 2008 Sep 25;51(18):5522-32.The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer .Folkes AJ, Ahmadi K, Alderton WK, Alix S, Baker SJ, Box G, Chuckowree IS, Clarke PA, Depledge P, Eccles SA, Friedman LS, Hayes A, Hancox TC, Kugendradas A, Lensun L, Moore P, Olivero AG, Pang J, Patel S, Pergl-Wilson GH, Raynaud FI, Robson A, Saghir N, Salphati L, Sohal S, Ultsch MH, Valenti M, Wallweber HJ, Wan NC, Wiesmann C, Workman P, Zhyvoloup A, Zvelebil MJ, Shuttleworth SJ.

KIN268 C1=CC(=CC(=C1N1)C(=C(C=1)C=C1)N(C1=O)C(C=CC1C)=CC=1C)N1C=C(N=C1)C

Chemistry 19 Preparation of substituted benzonaphthyridinones as mTOR modulatorsBy Gray, Nathanael; Chang, Jae Won; Zhang, Jianming; Thoreen, Carson C.; Kang, Seong Woo Anthony; Sabatini, David M.; Liu, QingsongFrom PCT Int. Appl. (2010), WO 2010044885 A2 20100422. Language: English, Database: CAPLUS

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Supplementary Table 2

Rab ID KIN-193

Compound Concentration (µM) 10

AAK1 91ABL1(E255K)-phosphorylated 100ABL1(F317I)-nonphosphorylated 100ABL1(F317I)-phosphorylated 100ABL1(F317L)-nonphosphorylated 100ABL1(F317L)-phosphorylated 13ABL1(H396P)-nonphosphorylated 78ABL1(H396P)-phosphorylated 100ABL1(M351T)-phosphorylated 100ABL1(Q252H)-nonphosphorylated 80ABL1(Q252H)-phosphorylated 83ABL1(T315I)-nonphosphorylated 100ABL1(T315I)-phosphorylated 100ABL1(Y253F)-phosphorylated 100ABL1-nonphosphorylated 69ABL1-phosphorylated 100ABL2 100ACVR1 100ACVR1B 100ACVR2A 95ACVR2B 100ACVRL1 100ADCK3 70ADCK4 95AKT1 100AKT2 100AKT3 80ALK 100AMPK-alpha1 62AMPK-alpha2 91ANKK1 100ARK5 100ASK1 100ASK2 94AURKA 75AURKB 76AURKC 91AXL 100BIKE 100BLK 100BMPR1A 79BMPR1B 89BMPR2 84BMX 82BRAF 74BRAF(V600E) 80BRK 15BRSK1 100BRSK2 94BTK 80CAMK1 94CAMK1D 93CAMK1G 100CAMK2A 66CAMK2B 89CAMK2D 100CAMK2G 87CAMK4 100CAMKK1 91CAMKK2 72CASK 100CDC2L1 100CDC2L2 100CDC2L5 100CDK11 100CDK2 64CDK3 92CDK4-cyclinD1 38CDK4-cyclinD3 62CDK5 100CDK7 90CDK8 100CDK9 89CDKL1 100CDKL2 100CDKL3 96CDKL5 82CHEK1 64CHEK2 100CIT 88CLK1 56

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CLK2 100CLK3 95CLK4 100CSF1R 55CSK 98CSNK1A1 100CSNK1A1L 94CSNK1D 57CSNK1E 92CSNK1G1 77CSNK1G2 100CSNK1G3 95CSNK2A1 66CSNK2A2 64CTK 57DAPK1 100DAPK2 74DAPK3 78DCAMKL1 100DCAMKL2 100DCAMKL3 100DDR1 81DDR2 100DLK 98DMPK 95DMPK2 99DRAK1 87DRAK2 100DYRK1A 99DYRK1B 100DYRK2 72EGFR 100EGFR(E746-A750del) 100EGFR(G719C) 100EGFR(G719S) 100EGFR(L747-E749del, A750P) 100EGFR(L747-S752del, P753S) 100EGFR(L747-T751del,Sins) 68EGFR(L858R) 96EGFR(L858R,T790M) 100EGFR(L861Q) 76EGFR(S752-I759del) 100EGFR(T790M) 100EIF2AK1 100EPHA1 100EPHA2 99EPHA3 85EPHA4 91EPHA5 100EPHA6 100EPHA7 87EPHA8 82EPHB1 99EPHB2 100EPHB3 100EPHB4 95EPHB6 40ERBB2 96ERBB3 100ERBB4 94ERK1 94ERK2 100ERK3 78ERK4 82ERK5 100ERK8 100ERN1 100FAK 80FER 81FES 100FGFR1 97FGFR2 100FGFR3 100FGFR3(G697C) 100FGFR4 40FGR 76FLT1 96FLT3 4.2FLT3(D835H) 32FLT3(D835Y) 24FLT3(ITD) 40FLT3(K663Q) 15FLT3(N841I) 26FLT3(R834Q) 100FLT4 100FRK 47FYN 41

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GAK 83GCN2(Kin.Dom.2,S808G) 78GRK1 81GRK4 80GRK7 100GSK3A 100GSK3B 100HCK 60HIPK1 87HIPK2 77HIPK3 68HIPK4 56HPK1 90HUNK 94ICK 100IGF1R 100IKK-alpha 69IKK-beta 95IKK-epsilon 100INSR 79INSRR 100IRAK1 100IRAK3 75IRAK4 100ITK 100JAK1(JH1domain-catalytic) 70JAK1(JH2domain-pseudokinase) 100JAK2(JH1domain-catalytic) 71JAK3(JH1domain-catalytic) 100JNK1 100JNK2 69JNK3 66KIT 69KIT(A829P) 87KIT(D816H) 93KIT(D816V) 100KIT(L576P) 90KIT(V559D) 93KIT(V559D,T670I) 64KIT(V559D,V654A) 100LATS1 60LATS2 97LCK 81LIMK1 100LIMK2 100LKB1 97LOK 71LRRK2 97LRRK2(G2019S) 90LTK 61LYN 89LZK 100MAK 100MAP3K1 100MAP3K15 55MAP3K2 88MAP3K3 77MAP3K4 100MAP4K2 97MAP4K3 99MAP4K4 98MAP4K5 92MAPKAPK2 95MAPKAPK5 90MARK1 90MARK2 100MARK3 95MARK4 100MAST1 54MEK1 100MEK2 98MEK3 99MEK4 70MEK5 100MEK6 91MELK 100MERTK 100MET 95MET(M1250T) 67MET(Y1235D) 93MINK 100MKK7 100MKNK1 31MKNK2 100MLCK 82MLK1 100MLK2 96MLK3 95

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MRCKA 100MRCKB 100MST1 72MST1R 96MST2 97MST3 85MST4 100MTOR 18MUSK 100MYLK 43MYLK2 94MYLK4 75MYO3A 100MYO3B 51NDR1 84NDR2 92NEK1 100NEK11 68NEK2 100NEK3 65NEK4 94NEK5 100NEK6 100NEK7 98NEK9 94NIM1 100NLK 100OSR1 80p38-alpha 100p38-beta 100p38-delta 100p38-gamma 82PAK1 97PAK2 100PAK3 12PAK4 95PAK6 96PAK7 92PCTK1 100PCTK2 100PCTK3 83PDGFRA 100PDGFRB 58PDPK1 100PFCDPK1(P.falciparum) 75PFPK5(P.falciparum) 92PFTAIRE2 100PFTK1 100PHKG1 100PHKG2 67PIK3C2B 1PIK3C2G 16PIK3CA 0.5PIK3CB 0.5PIK3CD 10PIK3CG 0.2PIK4CB 89PIM1 100PIM2 83PIM3 100PIP5K1A 100PIP5K1C 55PIP5K2B 84PIP5K2C 94PKAC-alpha 100PKAC-beta 62PKMYT1 99PKN1 100PKN2 74PKNB(M.tuberculosis) 100PLK1 55PLK2 100PLK3 94PLK4 100PRKCD 100PRKCE 100PRKCH 95PRKCI 94PRKCQ 100PRKD1 100PRKD2 97PRKD3 85PRKG1 79PRKG2 100PRKR 100PRKX 100PRP4 100PYK2 90

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QSK 87RAF1 97RET 96RET(M918T) 100RET(V804L) 100RET(V804M) 99RIOK1 75RIOK2 35RIOK3 100RIPK1 100RIPK2 52RIPK4 87RIPK5 90ROCK1 90ROCK2 89ROS1 84RPS6KA4(Kin.Dom.1-N-terminal) 93RPS6KA4(Kin.Dom.2-C-terminal) 83RPS6KA5(Kin.Dom.1-N-terminal) 100RPS6KA5(Kin.Dom.2-C-terminal) 100RSK1(Kin.Dom.1-N-terminal) 67RSK1(Kin.Dom.2-C-terminal) 76RSK2(Kin.Dom.1-N-terminal) 100RSK3(Kin.Dom.1-N-terminal) 100RSK3(Kin.Dom.2-C-terminal) 100RSK4(Kin.Dom.1-N-terminal) 80RSK4(Kin.Dom.2-C-terminal) 71S6K1 100SBK1 100SgK110 68SGK3 100SIK 100SIK2 90SLK 85SNARK 100SNRK 54SRC 100SRMS 100SRPK1 100SRPK2 88SRPK3 83STK16 99STK33 100STK35 96STK36 82STK39 58SYK 90TAK1 100TAOK1 79TAOK2 89TAOK3 95TBK1 100TEC 91TESK1 100TGFBR1 100TGFBR2 100TIE1 100TIE2 94TLK1 100TLK2 100TNIK 97TNK1 91TNK2 100TNNI3K 15TRKA 69TRKB 81TRKC 75TRPM6 64TSSK1B 79TTK 88TXK 100TYK2(JH1domain-catalytic) 100TYK2(JH2domain-pseudokinase) 95TYRO3 100ULK1 73ULK2 100ULK3 100VEGFR2 100VRK2 83WEE1 88WEE2 100YANK1 100YANK2 100YANK3 89YES 100YSK1 100YSK4 100ZAK 100

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ZAP70 72

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CellLine Organ PTEN PTENbin IC50uM

RXF393 Kidney p.?::0 1 0.01119735SW982 Misc wt::0<cn<8 0 0.03566252KURAMOCHI Ovary wt::0<cn<8 0 0.10579733A498 Kidney wt::0<cn<8 0 0.12071511MDA‐MB‐415 Breast p.C136Y::nci 1 0.17253537VMRC‐RCZ Kidney wt::0<cn<8 0 0.17409102ZR‐75‐30 Breast wt::0<cn<8 0 0.19089247J82 Bladder p.N212fs*1::0 1 0.49908643T47D Breast wt::0<cn<8 0 0.51698625BT‐20 Breast wt::nci 0 0.6055513OS‐RC‐2 Kidney p.?::nci 1 0.62938256NIH:OVCAR‐3 Ovary wt::0<cn<8 0 0.68781801SK‐MES‐1 Lung:NSCLC wt::nci 0 0.79366803SCC‐9 Head&Neckwt::0<cn<8 0 0.84191013NCI‐H2342 Lung:NSCLC wt::0<cn<8 0 0.86118666HGC‐27 Stomach p.?::0 1 1.18503582CAMA‐1 Breast p.D92H::0<cn<8 1 1.20729461SK‐OV‐3 Ovary wt::nci 0 1.2120668MEL‐HO Skin wt::nci 0 1.23946149U‐2OS Bone wt::0<cn<8 0 1.26566794786‐O Kidney p.Q149*::nci 1 1.29019323NCI‐H650 Lung:NSCLC wt::0<cn<8 0 1.32132101GI‐1 CNS wt::nci 0 1.32386435Becker CNS wt::0<cn<8 0 1.3816715LXF‐289 Lung wt::0<cn<8 0 1.51646808CAL‐33 Head&Neckwt::0<cn<8 0 1.52215486MDA‐MB‐468 Breast p.?::nci 1 1.53208875CCF‐STTG1 Brain p.L112R::nci 1 1.53758499MFE‐296 Uterus wt::nci 0 1.5677618OCUB‐M Breast wt::nci 0 1.57977432D‐336MG CNS p.0?::0 1 1.62546674HCC70 Breast p.F90fs*9::nci 1 1.64259121639‐V Bladder wt::0<cn<8 0 1.70225697SNB75 CNS wt::nci 0 1.72358599LoVo Intescne wt::0<cn<8 0 1.72472738HSC‐2 Head&Neckwt::nci 0 1.75706886D‐542MG CNS p.R335*::nci 1 1.82314312CaSki Cervix wt::0<cn<8 0 1.85861577CAL‐39 Cervix wt::0<cn<8 0 1.95590304IGROV‐1 Ovary wt::0<cn<8 0 1.95810859

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Panc10.05 Pancreas wt::nci 0 2.05941096IGROV‐1 Ovary wt::0<cn<8 0 2.08442492CAL‐85‐1 Breast wt::nci 0 2.33850772IST‐MEL1 Skin wt::nci 0 2.40881759SW1088 Brain p.R55fs*1::0 1 2.50750692SK‐UT‐1 Muscle p.T319fs*1::0<cn<8 1 2.53240134DOK Head&Neckwt::0<cn<8 0 2.75666882SF‐295 Brain p.R233*::nci 1 2.84995157LN‐405 Brain p.R173C::nci 1 2.86544884NCI‐H2030 Lung:NSCLC wt::0<cn<8 0 2.97893543SK‐LMS‐1 Misc wt::0<cn<8 0 3.06275243G‐402 Kidney wt::0<cn<8 0 3.09378729HCC1569 Breast wt::nci 0 3.18735685Caki‐1 Kidney wt::0<cn<8 0 3.24362652NCI‐H1755 Lung:NSCLC wt::0<cn<8 0 3.2440028RKO Intescne wt::0<cn<8 0 3.27194628A101D Skin p.G165_*404del::0 1 3.28672294Calu‐3 Lung:NSCLC wt::0<cn<8 0 3.38554873BxPC‐3 Pancreas wt::nci 0 3.53533832MDA‐MB‐361 Breast wt::0<cn<8 0 3.55182303CFPAC‐1 Pancreas wt::0<cn<8 0 3.72858946H292 Lung wt::0<cn<8 0 3.73752265AN3CA Uterus p.R130fs*4::nci 1 3.7615985DOK Head&Neckwt::0<cn<8 0 3.76747871G‐401 Kidney wt::0<cn<8 0 3.9169567UACC‐893 Breast wt::nci 0 3.99242973NCI‐H520 Lung:NSCLC wt::nci 0 4.06408246KALS‐1 CNS p.R130*::nci 1 4.33471559SF126 CNS p.G129R::nci 1 4.39626361SW954 Vulva wt::0<cn<8 0 4.39996682KGN Ovary wt::0<cn<8 0 4.44730369GAMG Brain wt::nci 0 4.50246489TE‐15 Esophagus wt::nci 0 4.61161444NB69 NervousSystemwt::0<cn<8 0 4.65550318EFO‐21 Ovary wt::0<cn<8 0 4.90090558DMS273 Lung wt::nci 0 4.9066479BB30‐HNC H&N wt::nci 0 4.91421979NCI‐H2009 Lung:NSCLC wt::0<cn<8 0 4.96739223NCI‐H522 Lung:NSCLC wt::0<cn<8 0 5.0524031423132/87 Stomach wt::0<cn<8 0 5.11706483A‐204 Muscle wt::0<cn<8 0 5.12623771HCC38 Breast wt::0<cn<8 0 5.15286051

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BPH‐1 Prostate wt::0<cn<8 0 5.15954811MG‐63 Bone wt::0<cn<8 0 5.16946913HCC1954 Breast wt::0<cn<8 0 5.18540527T98G Brain wt::nci 0 5.51350204KNS‐42 CNS wt::0<cn<8 0 5.56780555H4 Brain p.0?::0 1 5.58796959BFTC‐909 Kidney wt::0<cn<8 0 5.71014833EFM‐19 Breast wt::nci 0 5.73484085NCI‐H157 Lung wt::nci 0 5.78618396CHL‐1 Skin wt::0<cn<8 0 5.82237352BHY Head&Neckwt::0<cn<8 0 5.94488984NCI‐H1734 Lung:NSCLC wt::nci 0 6.27304574EFO‐27 Ovary p.K267fs*9::0<cn<8 1 6.34042626DoTc24510 Cervix wt::0<cn<8 0 6.417842498‐MG‐BA CNS wt::nci 0 6.44318511SBC‐5 Lung wt::0<cn<8 0 6.5008374MEL‐JUSO Skin wt::0<cn<8 0 6.52762388HuCCT1 Liver wt::nci 0 6.56178717RCC10RGB Kidney wt::0<cn<8 0 6.64294906HCT116 Intescne wt::0<cn<8 0 6.70515746TE‐10 Esophagus wt::0<cn<8 0 6.81932846TCCSUP Bladder wt::0<cn<8 0 6.91003705CGTH‐W‐1 Thyroid wt::0<cn<8 0 7.1689629LB831‐BLC Bladder wt::nci 0 7.21367839KYSE‐270 Esophagus wt::nci 0 7.30042817EFO‐21 Ovary wt::0<cn<8 0 7.42998619BHY Head&Neckwt::0<cn<8 0 7.58205294KYSE‐270 Esophagus wt::nci 0 7.72440657KS‐1 CNS wt::0<cn<8 0 7.74942774D‐392MG CNS p.K197*::nci 1 7.83106879D‐247MG CNS p.?::nci 1 7.83401383KYSE‐510 Esophagus wt::0<cn<8 0 7.95860712SNU‐449 Liver wt::0<cn<8 0 7.9758482NCI‐H1648 Lung:NSCLC wt::0<cn<8 0 8.28279937COLO‐829 Skin p.?::0 1 8.38345399no‐10 CNS p.?::0 1 8.63726516ESS‐1 Uterus wt::0<cn<8 0 8.9093118Panc03.27 Pancreas wt::0<cn<8 0 8.91779751MDA‐MB‐453 Breast wt::0<cn<8 0 9.24584258BFTC‐909 Kidney wt::0<cn<8 0 9.29637928SK‐MEL‐3 Skin wt::nci 0 9.37337291NCI‐H1975 Lung:NSCLC wt::0<cn<8 0 9.44548642

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BT‐474 Breast wt::nci 0 9.79824218AGS Stomach wt::0<cn<8 0 9.9352198OAW28 Ovary wt::0<cn<8 0 9.96472145MZ1‐PC Pancreas wt::0<cn<8 0 9.98628848KINGS‐1 CNS wt::nci 0 10.1535663UACC‐62 Skin p.P248fs*5::nci 1 10.3382747K5 Thyroid wt::0<cn<8 0 10.3760369OE19 Esophagus wt::nci 0 10.5948285KOSC‐2cl3‐43 Head&Neckwt::nci 0 10.9120535EW‐16 Bone wt::0<cn<8 0 10.9239541DBTRG‐05MG Brain p.?::0 1 10.92674NCI‐H1563 Lung:NSCLC wt::0<cn<8 0 11.1812805Daoy Brain wt::nci 0 11.2106475NCI‐H1437 Lung:NSCLC wt::0<cn<8 0 11.5659218VA‐ES‐BJ Misc wt::0<cn<8 0 11.6184459SW684 Misc wt::0<cn<8 0 11.6779331HTC‐C3 Thyroid wt::0<cn<8 0 11.74792948305C Thyroid wt::0<cn<8 0 11.756579SNU‐387 Liver wt::nci 0 11.9038515YKG‐1 Brain p.?::nci 1 11.9218875SF268 CNS wt::nci 0 11.9622278COLO‐679 Skin wt::0<cn<8 0 11.9705444SW900 Lung:NSCLC wt::nci 0 12.3695153TE‐12 Esophagus wt::0<cn<8 0 12.4206573NOS‐1 Bone wt::0<cn<8 0 12.513274ES6 Bone wt::0<cn<8 0 12.7023117Panc08.13 Pancreas wt::nci 0 12.7747555UM‐UC‐3 Bladder p.0?::0 1 13.0292652BHT‐101 Thyroid wt::0<cn<8 0 13.1461771HOP92 Lung:NSCLC wt::0<cn<8 0 13.1900532CAL27 Head&Neckwt::0<cn<8 0 13.246005HLE Liver wt::0<cn<8 0 13.2492242ACN PNS p.N184fs*6::nci 1 13.4860929HEC‐1 Uterus wt::0<cn<8 0 13.5394548KLE Uterus wt::nci 0 13.9198238ABC‐1 Lung:NSCLC wt::0<cn<8 0 13.9501045Saos‐2 Bone wt::0<cn<8 0 14.3257555LCLC‐97TM1 Lung:NSCLC wt::0<cn<8 0 14.4486069BB65‐RCC Kidney wt::0<cn<8 0 14.4713235COR‐L105 Lung:NSCLC wt::0<cn<8 0 14.5588783TE‐9 Esophagus wt::nci 0 14.6732631BFTC‐905 Bladder wt::0<cn<8 0 15.2116716

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LB1047‐RCC Kidney wt::0<cn<8 0 15.5998297KYSE‐510 Esophagus wt::0<cn<8 0 15.7272677ETK‐1 Biliarytract wt::0<cn<8 0 15.8346567UMC‐11 Lung wt::0<cn<8 0 15.868722MMAC‐SF Skin wt::nci 0 16.2022966A2058 Skin p.V175fs*3::0<cn<8 1 16.4505679KYSE‐450 Esophagus wt::0<cn<8 0 16.6756238TE‐1 Esophagus wt::0<cn<8 0 16.9151725B‐CPAP Thyroid wt::0<cn<8 0 17.0840623AU565 Breast wt::nci 0 17.1497912RMG‐I Ovary wt::0<cn<8 0 17.4446847NB12 PNS wt::0<cn<8 0 17.6175401M059J Brain p.P204fs*17::nci 1 17.7807427NCI‐H358 Lung:NSCLC wt::0<cn<8 0 17.9165882KYSE‐150 Esophagus wt::0<cn<8 0 18.1920193GAK Skin wt::0<cn<8 0 18.2702856ACHN Kidney wt::0<cn<8 0 18.6231047HCC1395 Breast p.N212fs*1::0 1 18.6318783NCI‐H2347 Lung:NSCLC wt::0<cn<8 0 18.7570185FaDu Head&Neckwt::0<cn<8 0 18.8489461H28 Lung wt::0<cn<8 0 18.866163HOP‐62 Lung wt::nci 0 18.9128957RVH‐421 Skin p.?::0 1 19.2892703COLO‐680N Esophagus wt::0<cn<8 0 19.3642774D‐263MG CNS p.E314fs*3::nci 1 19.419156SW872 Misc p.0?::0 1 19.6038701BT‐549 Breast p.V275fs*1::nci 1 19.7844643H2052 Lung wt::0<cn<8 0 20.1324311RD Muscle wt::nci 0 20.464261NCI‐H2126 Lung wt::nci 0 20.7097996SK‐MEL‐30 Skin wt::nci 0 21.2250906COLO205 Intescne wt::0<cn<8 0 21.4779537RL95‐2 Uterus p.N323fs*21::0<cn<8 1 21.8388611SW48 Intescne wt::0<cn<8 0 21.9374671SH‐4 Skin wt::0<cn<8 0 22.5357965NCI‐H1650 Lung:NSCLC wt::0 1 23.4417355MFE‐280 Uterus wt::nci 0 23.4775583HOS Bone wt::0<cn<8 0 23.6477743SCC‐4 Head&Neckwt::0<cn<8 0 23.868438SBC‐5 Lung wt::0<cn<8 0 24.2162767CaR‐1 Intescne wt::0<cn<8 0 24.3147217LB996‐RCC Kidney wt::0<cn<8 0 25.070278

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OVCAR‐4 Ovary wt::0<cn<8 0 25.2513596DSH1 Bladder p.?::0 1 25.2981179no‐10 CNS p.?::0 1 25.4044156GMS‐10 Brain wt::nci 0 25.5260628NCI‐H522 Lung:NSCLC wt::0<cn<8 0 25.9523717647‐V Bladder wt::nci 0 26.4986291HT‐29 Intescne wt::0<cn<8 0 26.6494097SK‐LU‐1 Lung:NSCLC wt::0<cn<8 0 26.7034027SK‐HEP‐1 Liver wt::0<cn<8 0 26.8360464WM‐115 Skin p.?::0 1 26.8790185NCI‐H2452 Lung wt::0<cn<8 0 27.4678437Ca9‐22 Head&Neckwt::nci 0 27.5014299TGBC1TKB Biliarytract p.?::0 1 27.6700057KOSC‐2cl3‐43 Head&Neckwt::nci 0 27.7534734HMVII Skin wt::nci 0 28.4166716SW1573 Lung:NSCLC wt::0<cn<8 0 28.5714509KYSE‐520 Esophagus wt::nci 0 28.6632553CHP‐212 NervousSystemwt::0<cn<8 0 29.1917752NCI‐H1623 Lung:NSCLC wt::0<cn<8 0 29.2260957MDA‐MB‐175‐VII Breast wt::0<cn<8 0 29.9039028NCI‐H747 Intescne wt::0<cn<8 0 30.0782404KYSE‐70 Esophagus wt::0<cn<8 0 30.379833SW626 Ovary wt::nci 0 30.8220394A704 Kidney wt::0<cn<8 0 30.934467SW780 Bladder wt::nci 0 31.1959725OVCAR‐5 Ovary wt::0<cn<8 0 31.4471387A388 Unknown wt::0<cn<8 0 31.7074605SW13 Kidney wt::0<cn<8 0 31.7715108SK‐MEL‐28 Skin wt::nci 0 32.0034593MC‐IXC NervousSystemwt::0 1 32.2912082PC‐3 Prostate p.R55fs*1::0 1 32.8081185CAL‐72 Bone wt::0<cn<8 0 33.0587407HUTU‐80 Intescne wt::0<cn<8 0 33.2412641MFH‐ino Misc wt::0<cn<8 0 33.253732HCC1395 Breast p.N212fs*1::0 1 33.7173655NY Bone wt::nci 0 33.9348327TK10 Kidney wt::0<cn<8 0 34.0252876SKG‐IIIa Cervix wt::0<cn<8 0 34.1906427KLE Uterus wt::nci 0 34.6885964SCC‐4 Head&Neckwt::0<cn<8 0 35.737623A172 Brain p.R55fs*1::0 1 35.9369495MES‐SA Uterus wt::0<cn<8 0 36.7332743

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NCI‐H1355 Lung wt::0<cn<8 0 36.7731515LB771‐HNC H&N wt::0<cn<8 0 36.7778588Capan‐2 Pancreas wt::0<cn<8 0 37.8890821EKVX Lung wt::0<cn<8 0 38.1267448ES4 Bone wt::0<cn<8 0 38.9982978U‐118MG Brain p.?::nci 1 39.0581281NCI‐H1792 Lung:NSCLC wt::nci 0 39.9280466LS‐411N Intescne wt::0<cn<8 0 40.178057TE‐5 Esophagus wt::0<cn<8 0 40.3463931LC‐2‐ad Lung wt::0<cn<8 0 40.8949261GB‐1 CNS wt::nci 0 40.919184NCI‐H1993 Lung:NSCLC wt::0<cn<8 0 41.2330039PLC/PRF/5 Liver wt::nci 0 41.7923789NCI‐H2170 Lung:NSCLC wt::0<cn<8 0 41.9129983IPC‐298 Skin wt::0<cn<8 0 42.1594138SH‐4 Skin wt::0<cn<8 0 42.1908343DU145 Prostate wt::0<cn<8 0 42.3687474TCCSUP Bladder wt::0<cn<8 0 43.8432599KNS‐81‐FD CNS wt::nci 0 44.0601612GI‐ME‐N PNS wt::0<cn<8 0 45.1679155GCIY Stomach wt::nci 0 45.322065NCI‐H661 Lung:NSCLC wt::nci 0 46.8683215ECC12 Stomach wt::0<cn<8 0 47.1633921HT1376 Bladder wt::0<cn<8 0 48.0603254UO‐31 Kidney wt::0<cn<8 0 48.1711358UACC‐257 Skin wt::nci 0 48.6216546ONS‐76 CNS wt::nci 0 49.0027785NCI‐H2228 Lung:NSCLC wt::0<cn<8 0 49.3110898HT‐144 Skin p.?::0 1 50.9366142DK‐MG Brain wt::nci 0 51.8192136SW962 Vulva wt::0<cn<8 0 51.8622933RT‐112 Bladder wt::0<cn<8 0 51.8791513MZ7‐mel Skin wt::0<cn<8 0 52.1391445DK‐MG Brain wt::nci 0 52.2640628C3A Liver wt::0<cn<8 0 54.0892251SCC‐25 Head&Neckwt::0<cn<8 0 54.1664114DMS53 Lung wt::0<cn<8 0 54.1673864OAW42 Ovary wt::0<cn<8 0 54.9051966DV‐90 Lung:NSCLC wt::0<cn<8 0 55.2371094OVCAR‐8 Ovary wt::0<cn<8 0 56.2879793CAL‐12T Lung:NSCLC wt::0<cn<8 0 57.6090688no‐11 CNS p.Q17del::nci 1 58.3809128

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HCC1806 Breast wt::0<cn<8 0 59.5223576SBC‐5 Lung wt::0<cn<8 0 61.3458792SW837 Intescne wt::0<cn<8 0 61.4978368IST‐MES1 Lung wt::0<cn<8 0 61.6576309NCI‐H1693 Lung:NSCLC wt::nci 0 63.3248609SNG‐M Uterus p.V290fs*1::0<cn<8 1 63.7548972TE‐11 Esophagus wt::0<cn<8 0 64.4766408MDA‐MB‐231 Breast wt::0<cn<8 0 64.8485791Lu‐135 Lung wt::nci 0 65.0953423HT‐1197 Bladder wt::0<cn<8 0 66.0452425CAL‐51 Breast wt::0<cn<8 0 66.3301139ETK‐1 Biliarytract wt::0<cn<8 0 66.8571999NCI‐H727 Lung wt::0<cn<8 0 67.3034165NCI‐H838 Lung:NSCLC wt::0<cn<8 0 67.9842459EFE‐184 Uterus wt::0<cn<8 0 69.983325NCI‐H2405 Lung:NSCLC wt::0<cn<8 0 70.3570506IPC‐298 Skin wt::0<cn<8 0 70.4845122HT1376 Bladder wt::0<cn<8 0 73.4287832ETK‐1 Biliarytract wt::0<cn<8 0 74.0706228D‐502MG CNS wt::0<cn<8 0 74.1448046HO‐1‐N‐1 Head&Neckwt::0<cn<8 0 74.464686SJSA‐1 Bone wt::0<cn<8 0 74.47332448505C Thyroid wt::nci 0 75.0787078HMVII Skin wt::nci 0 75.0875676NCI‐H1703 Lung:NSCLC wt::0<cn<8 0 79.6773217ME‐180 Cervix wt::nci 0 80.5544215MG‐63 Bone wt::0<cn<8 0 80.6862357NCI‐H1793 Lung:NSCLC wt::0<cn<8 0 80.9614407A‐375 Skin wt::nci 0 81.9087645A549 Lung:NSCLC wt::0<cn<8 0 82.1395804ChaGo‐K‐1 Lung:NSCLC wt::0<cn<8 0 83.5001977FTC‐133 Thyroid p.R130*::nci 1 83.9482888CAL‐120 Breast wt::nci 0 85.3704481TGBC24TKB Biliarytract wt::0<cn<8 0 86.7466672LB373‐MEL‐D Skin wt::nci 0 87.7756388COLO‐678 Intescne wt::0<cn<8 0 91.1195153NCI‐H838 Lung:NSCLC wt::0<cn<8 0 92.942312YAPC Pancreas wt::0<cn<8 0 93.1647098NCI‐H2126 Lung wt::nci 0 93.6944541KYSE‐450 Esophagus wt::0<cn<8 0 95.0885916RO82‐W‐1 Thyroid wt::nci 0 96.5903655MKN1 Stomach wt::nci 0 98.5732572

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NUGC‐3 Stomach wt::nci 0 99.4146016LU99A Lung:NSCLC wt::0<cn<8 0 103.27424322RV1 Prostate wt::0<cn<8 0 104.861979NCI‐H810 Lung:NSCLC wt::nci 0 106.356005MEWO Skin wt::0<cn<8 0 106.410473LB2518‐MEL Skin wt::nci 0 106.701584Hs578T Breast wt::nci 0 108.807797NCI‐H441 Lung:NSCLC wt::nci 0 109.458557TGBC24TKB Biliarytract wt::0<cn<8 0 111.089813NCI‐H460 Lung:NSCLC wt::nci 0 114.645642MHH‐ES‐1 Bone wt::0<cn<8 0 115.939094IA‐LM Lung wt::nci 0 119.796683C‐4II Cervix wt::0<cn<8 0 121.146311IGR‐1 Skin wt::nci 0 121.354134COR‐L23 Lung:NSCLC wt::0<cn<8 0 122.087744CAL‐62 Thyroid wt::0<cn<8 0 124.482731HCE‐T Sinus wt::0<cn<8 0 124.715233SW1463 Intescne wt::0<cn<8 0 126.718488NCI‐H2122 Lung:NSCLC wt::0<cn<8 0 127.176896TE‐8 Esophagus wt::0<cn<8 0 127.651769MPP‐89 Lung wt::nci 0 128.615843CP66‐MEL Skin wt::nci 0 129.5427575637 Bladder wt::nci 0 130.089542SNU‐C2B Intescne wt::0<cn<8 0 130.334471GCT Miscellaneouswt::nci 0 132.817632HPAF‐II Pancreas wt::nci 0 143.315859SW620 Intescne wt::nci 0 145.327527HCE‐4 Esophagus wt::0<cn<8 0 147.954383SN‐12C Kidney wt::0<cn<8 0 148.414643DJM‐1 Skin wt::0<cn<8 0 151.994905AsPC‐1 Pancreas wt::0<cn<8 0 153.710198HCT‐15 Intescne wt::0<cn<8 0 154.42538U‐2OS Bone wt::0<cn<8 0 155.312SK‐MEL‐24 Skin p.?::0 1 155.612353OMC‐1 Cervix wt::0<cn<8 0 159.158888MES‐SA Uterus wt::0<cn<8 0 164.500071HUP‐T3 Pancreas wt::nci 0 166.62587ES8 Bone p.?::0 1 171.24598NCI‐H596 Lung:NSCLC wt::0<cn<8 0 176.051929UMC‐11 Lung wt::0<cn<8 0 177.087684PA‐1 Ovary wt::0<cn<8 0 182.194172HUP‐T4 Pancreas wt::0<cn<8 0 186.377838

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Ca9‐22 Head&Neckwt::nci 0 200.631923LS‐411N Intescne wt::0<cn<8 0 202.935258KYSE‐410 Esophagus wt::nci 0 206.599472HT‐3 Cervix wt::0<cn<8 0 218.399292SK‐N‐AS NervousSystemwt::0<cn<8 0 229.637964MKN28 Stomach wt::0<cn<8 0 233.083789NCI‐H727 Lung wt::0<cn<8 0 241.006041GT3TKB Stomach wt::nci 0 250.457188KYSE‐140 Esophagus wt::0<cn<8 0 253.432369HT55 Intescne wt::0<cn<8 0 255.997838MIAPaCa‐2 Pancreas wt::0<cn<8 0 257.404042SW620 Intescne wt::nci 0 260.633968NCI‐N87 Stomach wt::0<cn<8 0 272.052483CP50‐MEL‐B Skin p.P246fs*11::nci 1 280.695092A498 Kidney wt::0<cn<8 0 281.050959BEN Lung:NSCLC wt::0<cn<8 0 286.88803HSC‐3 Head&Neckwt::0<cn<8 0 287.346269PC‐14 Lung:NSCLC wt::nci 0 291.446659SiHa Cervix wt::0<cn<8 0 292.867708JEG‐3 Uterus wt::0<cn<8 0 293.500399Calu‐6 Lung wt::0<cn<8 0 308.730584EGI‐1 Liver wt::0<cn<8 0 313.41588KYSE‐140 Esophagus wt::0<cn<8 0 317.53943LS‐1034 Intescne wt::0<cn<8 0 320.19398HT1080 Miscellaneouswt::0<cn<8 0 325.934682MKN45 Stomach wt::0<cn<8 0 334.379642S‐117 Thyroid wt::nci 0 345.915318KU‐19‐19 Bladder wt::0<cn<8 0 353.548968A498 Kidney wt::0<cn<8 0 354.162554RCM‐1 Intescne wt::0<cn<8 0 354.809136SW1990 Pancreas wt::0<cn<8 0 369.223075COLO‐800 Skin wt::0<cn<8 0 370.490202RERF‐LC‐MS Lung:NSCLC wt::nci 0 391.218802SAS Head&Neckwt::0<cn<8 0 400.732451RCM‐1 Intescne wt::0<cn<8 0 418.264497LK‐2 Lung:NSCLC wt::nci 0 423.904418PSN1 Pancreas wt::0<cn<8 0 437.287118MCF7 Breast wt::0<cn<8 0 449.375122NCI‐N87 Stomach wt::0<cn<8 0 457.456135C32 Skin p.?::0 1 457.914278HCC2998 Intescne wt::0<cn<8 0 474.066212RT4 Bladder wt::0<cn<8 0 493.781445

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COLO741 Intescne wt::0<cn<8 0 498.484751HUP‐T4 Pancreas wt::0<cn<8 0 522.188691TYK‐nu Ovary wt::nci 0 532.323294LS‐123 Intescne wt::nci 0 554.694216