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(12) Patent Application Publication (10) Pub. No.: US 2011/0008347 A1 Ullrich Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2011/0008347 A1 Ullrich Et Al US 2011 0008347A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0008347 A1 Ullrich et al. (43) Pub. Date: Jan. 13, 2011 (54) CANCER-RELATED PROTEIN KINASES Publication Classification (51) Int. Cl. (75) Inventors: Axel Ullrich, Munich (DE); Jens A 6LX 39/395 (2006.01) Ruhe, Planegg (DE); Stefan Hart, C7H 2L/00 (2006.01) Singapore (SG); Sylvia Street, CI2O I/68 (2006.01) Planegg (DE); Chee Hong Wong, GOIN 33/53 (2006.01) Singapore (SG); Boon Tin Chua, C7H 2L/04 (2006.01) Singapore (SG); Kiat Han Ho, CI2N 5/10 (2006.01) Singapore (SG) CI2N 9/12 (2006.01) GOIN 33/573 (2006.01) Correspondence Address: A6IP 43/00 (2006.01) FOLEY & LARDNER LLP (52) U.S. Cl. ........ 424/139.1:536/23.2:435/6: 435/721: P.O. BOX80278 536/24.3; 435/325; 435/194; 435/7.4 SAN DIEGO, CA 92138-0278 (US) (57) ABSTRACT The present invention relates to mutant kinase polypeptides (73) Assignee: Agency for Science Technology and kinase variants selected from the group consisting of and Research AATYK (AATK), ABL1, ACK1, ALK, ARG, AXL, BMX, BRK, BTK, CCK4, CSFR1, CSK, DDR1, DDR2, EGFR, (21) Appl. No.: 12/517,050 EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6, FAK, FER, FES, FGFR1, FGFR2, FGFR4, FLT3, (22) PCT Filed: Dec. 3, 2007 FRK, FYN, HER2, HER3, HER4, IGF1R, INSR, ITK, JAK1, JAK2, JAK3, LCK, LMTK2 (AATYK2/BREK), LYN, (86). PCT No.: PCT/SG2007/OOO412 MATK, MER, MET, NTRK1, NTRK2, NTRK3, PDGRFA, PDGFRB, PTK-9, PYK2, RET, RON, ROR1, ROR2, ROS, S371 (c)(1), RYK, STYK, SYK, TEC, TEK, TIE, TNK1, TXK, TYK2, (2), (4) Date: Sep. 23, 2010 TYRO3, VEGFR1, VEGFR2, VEGFR3, YES1, and ZAP70, nucleotide sequences encoding the mutant kinase polypep Related U.S. Application Data tides and kinase variants, as well as various products and methods useful for the diagnosis and treatment of various (60) Provisional application No. 60/868,173, filed on Dec. kinase-related diseases and conditions, including the screen 1, 2006. ing for and identification of novel protein kinase modulators. Number of Tissue Origin of Cell Lines Cell Lines bladder (BL) bone and soft tissue (BS) brain (BA) breast (BE) cervix and vulva (CW) colon (CO) endometrium and placenta head and neck (HN) hematopoietic and lymphoid system (HL) kidney (KI) liver (LI) lung (LU) ovary (OV) pancreas (PA) prostate (PR) skin (SK) stomach (ST) testes (TE) thyroid (TY) normal tissue (NO) Patent Application Publication Jan. 13, 2011 Sheet 1 of 306 US 2011/0008347 A1 Fig. 1A Number of Celines bladder (BL) bone and soft tissue (BS) brain (BA) breast (BE) Cervix and Vulva ( CV) colon (CO) endometrium and plaCenta head and neck (HN) hematopoietic and lymphoid system (HL) kidney (K) liver (L) lung (LU) ovary (OV) pancreas (PA) prostate (PR) skin (SK) stomach (ST) testes (TE) thyroid (TY) normal tissue (NO) Patent Application Publication Jan. 13, 2011 Sheet 2 of 306 US 2011/0008347 A1 Fig. 1B (continued from prev. page): Skin C-8161 Colo-16 TYRO3 346Nii P117OA: HER2 P117OA M518T# EPHA2 R876Hi T245A RON R813delinSROff P725Lif ROR1 M518T K838Tit STYK1 G204S G122Rht TNK1 M598celinSEVRSHXi PYK2 K838T FES S72 K129del 120 Somatic 100 Germline 80 60 40 20 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 1920 21 22 23 Absolute Number of Genetic Alterations per Cancer Cell TKT Patent Application Publication Jan. 13, 2011 Sheet 3 of 306 US 2011/0008347 A1 n au39 Patent Application Publication Jan. 13, 2011 Sheet 4 of 306 US 2011/0008347 A1 Frequency MS INS Protein Domains and Number of Polymorphisms therein Kinase 30 Cysteine-Rich 1 SH2 Transmembrane 3 Immunoglobulin 10 PT/TIG Juxtamembrane 13 Signal Peptide 1 Frizzled FNType III 8 Sema 3 WF SAM 3 Proline-Rich 9 Other Fig. 3C Germline Tissue Origin Alteration R521K (S15) G388R (S9) R988C (S. 10) T1010 (S.11) R780Q (SI 5) M518T T245A 346N V722 (SI 7) M598delinsEWRSHX R336O Y414fsX15 E971fsX67 V362F Patent Application Publication Jan. 13, 2011 Sheet 5 of 306 US 2011/0008347 A1 /|0||/|| (efied (GLIS)XALZGAJ (6IS)H9990 ‘Aelduuou,penu?uoo)o£ 61-I Patent Application Publication Jan. 13, 2011 Sheet 6 of 306 US 2011/0008347 A1 100% Fig. 4A EGFR R521 K EGFR K521 (HO) OEGFR K521 (HE) (t) 80% is 9 60% O > 2 40% c) s is 20% BA BE CV CO HN LU OV PA SK NO Tissue Origin 100% Fig. 4B TYK2 V362F TYK2 F362 (HO) OTYK2 F362 (HE) 80% t SPC 60% > 9 40% Cld o 20% - Tissue Origin Fig. 4C TNK1 M598delinSEVRSHX 100% TNK1 M598delinsEVRSHX (HO) DTNK1 M598delinsEVRSHX (HE) 40% BA BE CV HL LU OV PA SK NO Tissue Origin Patent Application Publication Jan. 13, 2011 Sheet 7 of 306 US 2011/0008347 A1 Protein Domains and Number of Somatic Mutations therein Kinase 71 Cysteine-Rich 6 Src-homology 2 4 Transmembrane 4 mmunoglobulin 7 Src-homology 3 3 Juxtamembrane 17 Signal Peptide 2 Other 95 FN type III 10 Sema 1 SAM 5 Proline-Rich 9 Fig. 5C (continued on next page) Tissue Origin Somatic Mutations (16) (22) (11) G719S (S 17) Q722X (S 18) P252S Y367C R849H N822K (SI 19) D981 E1027del (SI 20) A 1022 K1090del A1 OO6T E489K G417E K450R Q26X W531R K113O Patent Application Publication Jan. 13, 2011 Sheet 8 of 306 US 2011/0008347 A1 (OZIS)Iep/ZOLET?96C] (8)IS)XZZZO SZ9Zc| (6)IS)XAZZ8N (a6ed"Aelduuou,panu?uoo)og"61-I Patent Application Publication Jan. 13, 2011 Sheet 9 of 306 US 2011/0008347 A1 9·61-I |----E--No.--- XMAS Patent Application Publication Jan. 13, 2011 Sheet 10 of 306 US 2011/0008347 A1 Fig. 7 FGFR4 expression-fold change Fold <0.5 0.5-2.0 D2.0 change No. of patients 11 28 18 % of patients 19.3% 49.1% 31.6% Fig. 8 Expression Changes Between Normal and Tumor Tissues 41434547.49515355 57 1 3 5 7 9 11 13 15 1719 21 2325 272931 33 35 37 39 Patient Number Patent Application Publication Jan. 13, 2011 Sheet 11 of 306 US 2011/0008347 A1 Fig. 9 FGFR4-G388R HCC samples Controlpopulation Asian O 46.6% (27/58) (i. 29.3% (17/58) ssO O 24.1% (14/58) 6. Fig. 10 8.E+04 6.E--04 s D 2 4.E+04 L C 2.E--04 O -2.E--04 G/G G/R R/R FGFR4-G388R genotype Patent Application Publication Jan. 13, 2011 Sheet 12 of 306 US 2011/0008347 A1 FGF19 st imulat ion of AFP product O Hu7 e& Fig.11 FGF19 (ng/mL) FGF19 stimulation of AFP production in HepG2 ************* :::::::::::::::: 50 100 Fig. 12 Treatment Patent Application Publication Jan. 13, 2011 Sheet 13 of 306 US 2011/0008347 A1 Fig 13 ?::::::::::3333333 Controls iRNA FGFR4-siRNA Treatment Treatment uM Patent Application Publication Jan. 13, 2011 Sheet 14 of 306 US 2011/0008347 A1 Dose-response of PD173074 in Huh7 cells 125 Fig. 16 1OO 57O5 25 O O 10 20 30 40 50 60 Dose (uM) Patent Application Publication Jan. 13, 2011 Sheet 15 of 306 US 2011/0008347 A1 557 nisraenae 8],'fil Patent Application Publication Jan. 13, 2011 Sheet 16 of 306 US 2011/0008347 A1 pERK42/44 ERK42/44 STAT3 Patent Application Publication Jan. 13, 2011 Sheet 17 of 306 US 2011/0008347 A1 g ; Patent Application Publication Jan. 13, 2011 Sheet 18 of 306 US 2011/0008347 A1 upper: wn Phospho-Tyk2 (Y1054/55) 9 a S ; ; ; ; 3 S2 3 kDa . 17 as - Vy 13 OO kDa 17 130 O lower: B: Total Tyk2 Fig. 23 Patent Application Publication Jan. 13, 2011 Sheet 19 of 306 US 2011/0008347 A1 Fig. 24 ATCCIDSMZ Name number Obtained from Bladder HT-1376 bladder carcinoma CRL-1472 RT-4 bladder transitional-Cell HTB-2 papilloma SCa3ER bladder squamous cell HTB-3 carcinoma T-24 bladder transitional-Cell HTB-4 Carcinoma TCCSUP bladder transitional-Cell HTB-5 Carcinoma Bone and Soft Tissue MG-63 OsteoSarCOma CRL-1427 RD (1) rhabdomyosarcoma CCL-136 SaOS2 OsteoSarCOma HTB-85 TE-671 (1) rhabdomyosarcoma ACC-263 Brain 1321N1 astrocytoma ECACC A172 glioblastoma CRL-1620 ATCC CCF-STTG1 astrocytoma ECACC IMR-32 neuroblastoma DSMZ SF-126 glioblastoma Rutka et al., 1987 SF-763 glioblastoma Tissue Bank of the Brain Tumor Research Center, UCSF, CA, USA SF-767 glioblastoma Tissue Bank of the Brain Tumor Research Center, UCSF, CA, USA SH-SY-5Y neuroblastoma CRL-2266 ATCC SK-N-SH neuroblastoma HTB-11 ATCC SW-1088 astrocytoma HTB-12 ATCC T-98 G glioblastoma CRL-1690 ATCC U-118-MG glioblastoma HTB-15 ATCC U-138-MG glioblastoma HTB-16 ATCC U-373 glioblastoma HTB-17 ATCC U-1240 glioblastoma Nister et al., 1988 U-1242 glioblastoma Nister et al., 1988 (cont. on next page) Patent Application Publication Jan. 13, 2011 Sheet 20 of 306 US 2011/0008347 A1 Fig. 24 (cont. from prev. page) ATCCIDSMZ Obtained from number breast Carcinoma HTB-19 ATCC breast ductal Carcinoma HTB-2O ATCC breast ductal Carcinoma HTB-121 ATCC breast ductal Carcinoma HTB-122 ATCC breast carcinoma Pier Giorgio Natali Regina Elena Cancer Institute, Rome, Italy DU-44-75 breast Carcinoma HTB-123 ATCC HBL-100 breast epithelial cell line, tandemly HTB-124 ATCC integrated SV40 virus genome HS-578T breast ductal carcinoma HTB-126 ECACC MCF-7 breast carcinoma HTB-22 ATCC MDA-MB-157 breast medullary carcinoma HTB-24 ECACC MDA-MB-175W breast ductal carcinoma HTB-25 ATCC MDA-MB-231 breast carcinoma HTB-26 ATCC MDA-MB-361 breast carcinoma HTB-27 ATCC MDA-MB-415 breast Carcinoma HTB-128 DKFZ MDA-MB-435S breast ductal Carcinoma HTB-129 ATCC MDA-MB-436 breast carcinoma HTB-130 ATCC MDA-MB-453 breast carcinoma HTB-131 ATCC MDA-MB-468 breast Carcinoma HTB-132 ATCC SK-BR-3 breast Carcinoma HTE-30 ATCC T-47D breast ductal Carcinoma HTB-133 ATCC ZR-75-1 breast ductal carcinoma CRL-1500 ATCC ZR-75-30 breast ductal carcinoma CRL-1504 ATCC Cervix and Vulva vulva epidermoid carcinoma CRL-1555 cervix carcinoma HTB-31 Cervix carcinoma CRL-1595 Cervix carcinoma CRL-1550 Cervix carcinoma CCL-2.2 Cervix carcinoma HTB-32 cervix squamous cell carcinoma HTB-33 uterus SarCOma CRL-1976 cervix squamous cell carcinoma HTB-34 Cervix carcinoma HTB-35 Vulva Squamous Cell Carcinoma HTB-117 (cont.
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