Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Proceedings of the National Academy of Sciences of the United States of America

Volumn 111, Issue 45, 2014, Pages E4869-E4877

  Tan, Li ^a,b   Wang, Jun ^b   Tanizaki, Junko ^b   Huang, Zhifeng ^c,d   Aref, Amir R ^a,b   Rusan, Maria ^b,e   Zhu, Su Jie ^f   Zhang, Yiyun ^a,g   Ercan, Dalia ^b   Liao, Rachel G ^b,h   Capelletti, Marzia ^b   Zhou, Wenjun ^a,b   Hur, Wooyoung ^a,b,i   Kim, Namdoo ^j   Sim, Taebo ^i,k   Gaudet, Suzanne ^a,b   Barbie, David A ^b   Yeh, Jing Ruey Joanna ^a,g   Yun, Cai Hong ^f   Hammerman, Peter S ^b,h   Mohammadi, Moosa ^c   Jänne, Pasi A ^b   Gray, Nathanael S ^a,b   more..

^a HARVARD MEDICAL SCHOOL   (United States)

^b DANA FARBER CANCER INSTITUTE   (United States)

^c NEW YORK UNIVERSITY SCHOOL OF MEDICINE   (United States)

^d WENZHOU MEDICAL UNIVERSITY   (China)

^e AARHUS UNIVERSITY   (Denmark)

^f PEKING UNIVERSITY HEALTH SCIENCE CENTER   (China)

^g MASSACHUSETTS GENERAL HOSPITAL   (United States)

^h BROAD INSTITUTE OF MIT AND HARVARD   (United States)

ⁱ Korea Institute of Science and Technology   (South Korea)

^j Daegu Gyeongbuk Medical Innovation Foundation   (South Korea)

^k Korea University   (South Korea)

more..

Author keywords

Cancer drug resistance; Drug discovery; Kinase inhibitor; Structure based drug design

Indexed keywords

1 TERT BUTYL 3 [6 (3,5 DIMETHOXYPHENYL) 2 (4 DIETHYLAMINOBUTYLAMINO)PYRIDO[2,3 D]PYRIMIDIN 7 YL]UREA; 3 (2,6 DICHLORO 3,5 DIMETHOXYPHENYL) 1 [6 [[4 (4 ETHYL 1 PIPERAZINYL)PHENYL]AMINO] 4 PYRIMIDINYL] 1 METHYLUREA; AFATINIB; ANTINEOPLASTIC AGENT; AZD 4547; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; FGFR IRREVERSIBLE INHIBITOR 2; FGFR IRREVERSIBLE INHIBITOR 3; FIBROBLAST GROWTH FACTOR RECEPTOR 1; FIBROBLAST GROWTH FACTOR RECEPTOR 2; FIBROBLAST GROWTH FACTOR RECEPTOR 4; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; N [3 [[5 CHLORO 2 [[2 METHOXY 4 (4 METHYL 1 PIPERAZINYL)PHENYL]AMINO] 4 PYRIMIDINYL]OXY]PHENYL]ACRYLAMIDE; PROTEIN KINASE B; UNCLASSIFIED DRUG; VASCULOTROPIN RECEPTOR 1; VASCULOTROPIN RECEPTOR 3; EGFR PROTEIN, HUMAN; FGFR1 PROTEIN, HUMAN; FGFR2 PROTEIN, HUMAN; FGFR4 PROTEIN, HUMAN; PROTEIN KINASE INHIBITOR;

ANIMAL CELL; ANIMAL EXPERIMENT; ANTIPROLIFERATIVE ACTIVITY; ARTICLE; AUTOPHOSPHORYLATION; CANCER CELL LINE; CANCER INHIBITION; CANCER RESISTANCE; CELL PROLIFERATION; CELL SURVIVAL; CONCENTRATION RESPONSE; CONFORMATIONAL TRANSITION; CONTROLLED STUDY; CRYSTAL STRUCTURE; DIVERSIFYING SELECTION; DRUG BINDING; DRUG DESIGN; DRUG EFFICACY; DRUG POTENCY; DRUG SELECTIVITY; EC50; EMBRYO; ENZYME ACTIVATION; FEMALE; GENE INACTIVATION; HUMAN; HUMAN CELL; HYDROGEN BOND; IC50; IN VIVO STUDY; INHIBITION KINETICS; MALE; MORPHOGENESIS; MOUSE; NONHUMAN; PHENOTYPE; PROTEIN CONFORMATION; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; PROTEIN TARGETING; SIGNAL TRANSDUCTION; ZEBRA FISH; AMINO ACID SUBSTITUTION; ANTAGONISTS AND INHIBITORS; BINDING SITE; CHEMISTRY; DRUG EFFECTS; DRUG RESISTANCE; ENZYMOLOGY; GENETICS; METABOLISM; MISSENSE MUTATION; NEOPLASMS; PATHOLOGY; STRUCTURE ACTIVITY RELATION; TUMOR CELL LINE; X RAY CRYSTALLOGRAPHY;

AMINO ACID SUBSTITUTION; ANTINEOPLASTIC AGENTS; BINDING SITES; CELL LINE, TUMOR; CRYSTALLOGRAPHY, X-RAY; DRUG RESISTANCE, NEOPLASM; HUMANS; MUTATION, MISSENSE; NEOPLASMS; PROTEIN KINASE INHIBITORS; RECEPTOR, EPIDERMAL GROWTH FACTOR; RECEPTOR, FIBROBLAST GROWTH FACTOR, TYPE 1; RECEPTOR, FIBROBLAST GROWTH FACTOR, TYPE 2; RECEPTOR, FIBROBLAST GROWTH FACTOR, TYPE 4; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84909594628     PISSN: 00278424     EISSN: 10916490     Source Type: Journal    
DOI: 10.1073/pnas.1403438111     Document Type: Article

References (95)

1. Breccia M, Alimena G (2010) Nilotinib: A second-generation tyrosine kinase inhibitor for chronic myeloid leukemia. Leuk Res 34(2):129-134.
2. O'Hare T, et al. (2004) Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: Implications for CML. Blood 104(8):2532-2539.
3. Solca F, et al. (2012) Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther 343(2):342-350.
4. Zhou W, et al. (2009) Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature 462(7276):1070-1074.
5. Tiong KH, Mah LY, Leong CO (2013) Functional roles of fibroblast growth factor receptors (FGFRs) signaling in human cancers. Apoptosis 18(12):1447-1468.
6. Brooks AN, Kilgour E, Smith PD (2012) Molecular pathways: Fibroblast growth factor signaling: A new therapeutic opportunity in cancer. Clin Cancer Res 18(7):1855-1862.
7. Richette P, Bardin T, Stheneur C (2008) Achondroplasia: From genotype to phenotype. Joint Bone Spine 75(2):125-130.
8. Harding MJ, Nechiporuk AV (2012) Fgfr-Ras-MAPK signaling is required for apical constriction via apical positioning of Rho-associated kinase during mechanosensory organ formation. Development 139(17):3130-3135.
9. Ota S, Tonou-Fujimori N, Yamasu K (2009) The roles of the FGF signal in zebrafish embryos analyzed using constitutive activation and dominant-negative suppression of different FGF receptors. Mech Dev 126(1-2):1-17.
10. Böttcher RT, Niehrs C (2005) Fibroblast growth factor signaling during early vertebrate development. Endocr Rev 26(1):63-77.
11. Dieci MV, Arnedos M, Andre F, Soria JC (2013) Fibroblast growth factor receptor inhibitors as a cancer treatment: From a biologic rationale to medical perspectives. Cancer Discov 3(3):264-279.
12. Etienne A, et al. (2007) Combined translocation with ZNF198-FGFR1 gene fusion and deletion of potential tumor suppressors in a myeloproliferative disorder. Cancer Genet Cytogenet 173(2):154-158.
13. Singh D, et al. (2012) Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 337(6099):1231-1235.
14. Kim Y, et al. (2014) Integrative and comparative genomic analysis of lung squamous cell carcinomas in East Asian patients. J Clin Oncol 32(2):121-128.
15. Wu YM, et al. (2013) Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov 3(6):636-647.
16. Majewski IJ, et al. (2013) Identification of recurrent FGFR3 fusion genes in lung cancer through kinome-centred RNA sequencing. J Pathol 230(3):270-276.
17. Liao RG, et al. (2013) Inhibitor-sensitive FGFR2 and FGFR3 mutations in lung squamous cell carcinoma. Cancer Res 73(16):5195-5205.
18. Gatius S, et al. (2011) FGFR2 alterations in endometrial carcinoma. Mod Pathol 24(11):1500-1510.
19. Byron SA, et al. (2013) The N550K/H mutations in FGFR2 confer differential resistance to PD173074, dovitinib, and ponatinib ATP-competitive inhibitors. Neoplasia 15(8):975-988.
20. Roidl A, et al. (2010) The FGFR4 Y367C mutant is a dominant oncogene in MDA-MB453 breast cancer cells. Oncogene 29(10):1543-1552.
21. Shen YY, et al. (2013) Fibroblast growth factor receptor 4 Gly388Arg polymorphism in Chinese gastric cancer patients. World J Gastroenterol 19(28):4568-4575.
22. Ezzat S, et al. (2013) The cancer-associated FGFR4-G388R polymorphism enhances pancreatic insulin secretion and modifies the risk of diabetes. Cell Metab 17(6):929-940.
23. Taylor JG, 6th, et al. (2009) Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models. J Clin Invest 119(11):3395-3407.
24. Katoh M, Nakagama H (2014) FGF receptors: Cancer biology and therapeutics. Med Res Rev 34(2):280-300.
25. Weiss J, et al. (2010) Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med 2(62):62ra93.
26. Tsimafeyeu I, Demidov L, Stepanova E, Wynn N, Ta H (2011) Overexpression of fibroblast growth factor receptors FGFR1 and FGFR2 in renal cell carcinoma. Scand J Urol Nephrol 45(3):190-195.
27. Sato T, et al. (2009) Overexpression of the fibroblast growth factor receptor-1 gene correlates with liver metastasis in colorectal cancer. Oncol Rep 21(1):211-216.
28. Cottoni F, et al. (2009) Overexpression of the fibroblast growth factor receptor 2-IIIc in Kaposi's sarcoma. J Dermatol Sci 53(1):65-68.
29. Matsuda Y, Hagio M, Seya T, Ishiwata T (2012) Fibroblast growth factor receptor 2 IIIc as a therapeutic target for colorectal cancer cells. Mol Cancer Ther 11(9):2010-2020.
30. Gómez-Román JJ, et al. (2005) Fibroblast growth factor receptor 3 is overexpressed in urinary tract carcinomas and modulates the neoplastic cell growth. Clin Cancer Res 11(2 Pt 1):459-465.
31. Henson BJ, Gollin SM (2010) Overexpression of KLF13 and FGFR3 in oral cancer cells. Cytogenet Genome Res 128(4):192-198.
32. Kalff A, Spencer A (2012) The t (4;14) translocation and FGFR3 overexpression in multiple myeloma: Prognostic implications and current clinical strategies. Blood Cancer J 2:e89.
33. Ho HK, et al. (2009) Fibroblast growth factor receptor 4 regulates proliferation, antiapoptosis and alpha-fetoprotein secretion during hepatocellular carcinoma progression and represents a potential target for therapeutic intervention. J Hepatol 50(1):118-127.
34. Motoda N, et al. (2011) Overexpression of fibroblast growth factor receptor 4 in highgrade pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma. Int J Oncol 38(1):133-143.
35. Poh W, et al. (2012) Klotho-beta overexpression as a novel target for suppressing proliferation and fibroblast growth factor receptor-4 signaling in hepatocellular carcinoma. Mol Cancer 11(14):1-10.
36. Zaid TM, et al. (2013) Identification of FGFR4 as a potential therapeutic target for advanced-stage, high-grade serous ovarian cancer. Clin Cancer Res 19(4):809-820.
37. Ye YW, et al. (2011) Fibroblast growth factor receptor 4 regulates proliferation and antiapoptosis during gastric cancer progression. Cancer 117(23):5304-5313.
38. Lee HJ, et al. (2014) Drug resistance via feedback activation of Stat3 in oncogeneaddicted cancer cells. Cancer Cell 26(2):207-221.
39. Guagnano V, et al. (2011) Discovery of 3-(2, 6-dichloro-3, 5-dimethoxy-phenyl)-1-6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J Med Chem 54(20):7066-7083.
40. Wasag B, Lierman E, Meeus P, Cools J, Vandenberghe P (2011) The kinase inhibitor TKI258 is active against the novel CUX1-FGFR1 fusion detected in a patient with T-lymphoblastic leukemia/lymphoma and t (7;8) (q22;p11). Haematologica 96(6):922-926.
41. Zhao G, et al. (2011) A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models. Mol Cancer Ther 10(11):2200-2210.
42. Gavine PR, et al. (2012) AZD4547: An orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family. Cancer Res 72(8):2045-2056.
43. Zhou W, et al. (2010) A structure-guided approach to creating covalent FGFR inhibitors. Chem Biol 17(3):285-295.
44. Bixby D, Talpaz M (2009) Mechanisms of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia and recent therapeutic strategies to overcome resistance. Hematology (Am Soc Hematol Educ Program) 2009:461-476.
45. Weisberg E, et al. (2010) Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRalpha, Kit, and Src kinases: Novel type II inhibitor of gatekeeper mutants. Blood 115(21):4206-4216.
46. Yun CH, et al. (2008) The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA 105(6):2070-2075.
47. Schüttelkopf AW, van Aalten DM (2004) PRODRG: A tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr D Biol Crystallogr 60(Pt 8):1355-1363.
48. Chell V, et al. (2013) Tumour cell responses to new fibroblast growth factor receptor tyrosine kinase inhibitors and identification of a gatekeeper mutation in FGFR3 as a mechanism of acquired resistance. Oncogene 32(25):3059-3070.
49. Shukla N, et al. (2012) Oncogene mutation profiling of pediatric solid tumors reveals significant subsets of embryonal rhabdomyosarcoma and neuroblastoma with mutated genes in growth signaling pathways. Clin Cancer Res 18(3):748-757.
50. Ang D, et al. (2014) Novel mutations in neuroendocrine carcinoma of the breast: Possible therapeutic targets. Diagn Mol Pathol.
51. Kammasud N, et al. (2007) Novel inhibitor for fibroblast growth factor receptor tyrosine kinase. Bioorg Med Chem Lett 17(17):4812-4818.
52. Jansma A, et al. (2007) Verification of a designed intramolecular hydrogen bond in a drug scaffold by nuclear magnetic resonance spectroscopy. J Med Chem 50(24):5875-5877.
53. Goldstein DM, Gray NS, Zarrinkar PP (2008) High-throughput kinase profiling as a platform for drug discovery. Nat Rev Drug Discov 7(5):391-397.
54. Miduturu CV, et al. (2011) High-throughput kinase profiling: A more efficient approach toward the discovery of new kinase inhibitors. Chem Biol 18(7):868-879.
55. Lebakken CS, et al. (2009) Development and applications of a broad-coverage, TR-FRET-based kinase binding assay platform. J Biomol Screen 14(8):924-935.
56. Warmuth M, Kim S, Gu XJ, Xia G, Adrián F (2007) Ba/F3 cells and their use in kinase drug discovery. Curr Opin Oncol 19(1):55-60.
57. Reintjes N, et al. (2013) Activating somatic FGFR2 mutations in breast cancer. PLoS ONE 8(3):e60264.
58. Li D, et al. (2008) BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27(34):4702-4711.
59. Leproult E, Barluenga S, Moras D, Wurtz JM, Winssinger N (2011) Cysteine mapping in conformationally distinct kinase nucleotide binding sites: Application to the design of selective covalent inhibitors. J Med Chem 54(5):1347-1355.
60. Liu Y, Gray NS (2006) Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol 2(7):358-364.
61. Yun CH, et al. (2007) Structures of lung cancer-derived EGFR mutants and inhibitor complexes: Mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell 11(3):217-227.
62. 790 mutant. J Med Chem 55(6):2711-2723.
63. Dey JH, et al. (2010) Targeting fibroblast growth factor receptors blocks PI3K/AKT signaling, induces apoptosis, and impairs mammary tumor outgrowth and metastasis. Cancer Res 70(10):4151-4162.
64. Cole C, et al. (2010) Inhibition of FGFR2 and FGFR1 increases cisplatin sensitivity in ovarian cancer. Cancer Biol Ther 10(5):495-504.
65. Sewell JM, Macleod KG, Ritchie A, Smyth JF, Langdon SP (2002) Targeting the EGF receptor in ovarian cancer with the tyrosine kinase inhibitor ZD 1839("Iressa") Br J Cancer 86(3):456-462.
66. Aref AR, et al. (2013) Screening therapeutic EMT blocking agents in a three-dimensional microenvironment. Integr Biol (Camb) 5(2):381-389.
67. Itoh N (2007) The Fgf families in humans, mice, and zebrafish: Their evolutional processes and roles in development, metabolism, and disease. Biol Pharm Bull 30(10):1819-1825.
68. Turkington RC, et al. (2014) Fibroblast growth factor receptor 4 (FGFR4): Atargetable regulator of drug resistance in colorectal cancer. Cell Death Dis 5:e1046.
69. Miura S, et al. (2012) Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma. BMC Cancer 12(56):1-15.
70. Peláez-García A, et al. (2013) FGFR4 role in epithelial-mesenchymal transition and its therapeutic value in colorectal cancer. PLoS ONE 8(5):e63695.
71. Agarwal D, et al.; kConFab Investigators; Australian Ovarian Cancer Study Group; GENICA Network; TNBCC (2014) FGF receptor genes and breast cancer susceptibility: Results from the Breast Cancer Association Consortium. Br J Cancer 110(4):1088-1100.
72. Cheng AL, Shen YC, Zhu AX (2011) Targeting fibroblast growth factor receptor signaling in hepatocellular carcinoma. Oncology 81(5-6):372-380.
73. French DM, et al. (2012) Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models. PLoS ONE 7(5):e36713.
74. Ito F (2011) Foreword. Target therapy for cancer: Anti-cancer drugs targeting growthfactor signaling molecules. Biol Pharm Bull 34(12):1773.
75. Slattery ML, et al. (2013) Associations with growth factor genes (FGF1, FGF2, PDGFB, FGFR2, NRG2, EGF, ERBB2) with breast cancer risk and survival: The Breast Cancer Health Disparities Study. Breast Cancer Res Treat 140(3):587-601.
76. Kono SA, Marshall ME, Ware KE, Heasley LE (2009) The fibroblast growth factor receptor signaling pathway as a mediator of intrinsic resistance to EGFR-specific tyrosine kinase inhibitors in non-small cell lung cancer. Drug Resist Updat 12(4-5):95-102.
77. Tai AL, et al. (2006) Co-overexpression of fibroblast growth factor 3 and epidermal growth factor receptor is correlated with the development of nonsmall cell lung carcinoma. Cancer 106(1):146-155.
78. Terai H, et al. (2013) Activation of the FGF2-FGFR1 autocrine pathway: A novel mechanism of acquired resistance to gefitinib in NSCLC. Mol Cancer Res 11(7):759-767.
79. Ware KE, etal. (2010) Rapidly acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines through de-repression of FGFR2 and FGFR3 expression. PLoS ONE 5(11):e14117.
80. Herrera-Abreu MT, et al. (2013) Parallel RNA interference screens identify EGFR activation as an escape mechanism in FGFR3-mutant cancer. Cancer Discov 3(9):1058-1071.
81. Wang J, et al. (2014) Ligand-associated ERBB2/3 activation confers acquired resistance to FGFR inhibition in FGFR3-dependent cancer cells. Oncogene, 10.1038/onc.2014.161.
82. Issa A, et al. (2013) Combinatorial targeting of FGF and ErbB receptors blocks growth and metastatic spread of breast cancer models. Breast Cancer Res 15(R8):1-16.
83. Shimizu T, et al. (2012) The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer. Clin Cancer Res 18(8):2316-2325.
84. Wissner A, et al. (2007) Dual irreversible kinase inhibitors: Quinazoline-based inhibitors incorporating two independent reactive centers with each targeting different cysteine residues in the kinase domains of EGFR and VEGFR-2. Bioorg Med Chem 15(11):3635-3648.
85. Lipson D, et al. (2012) Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med 18(3):382-384.
86. Huang Z, et al. (2013) Structural mimicry of a-loop tyrosine phosphorylation by a pathogenic FGF receptor 3 mutation. Structure 21(10):1889-1896.
87. Minor W, Cymborowski M, Otwinowski Z, Chruszcz M (2006) HKL-3000: The integration of data reduction and structure solution-from diffraction images to an initial model in minutes. Acta Crystallogr D Biol Crystallogr 62(Pt 8):859-866.
88. Adams PD, et al. (2010) PHENIX: A comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr 66(Pt 2):213-221.
89. Chen H, et al. (2007) A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases. Mol Cell 27(5):717-730.
90. Emsley P, Lohkamp B, Scott WG, Cowtan K (2010) Features and development of Coot. Acta Crystallogr D Biol Crystallogr 66(Pt 4):486-501.
91. Kabsch W (1976) Solution for Best Rotation to Relate 2 Sets of Vectors. Acta Crystallogr A 32(Part 5):922-923.
92. Anonymous; Collaborative Computational Project, Number 4(1994) The CCP4 suite: Programs for protein crystallography. Acta Crystallogr D Biol Crystallogr 50(Pt 5):760-763.
93. DeLano WL (2002) The PyMOL User's Manual (DeLano Scientific, San Carlos, CA).
94. Farahat WA, et al. (2012) Ensemble analysis of angiogenic growth in three-dimensional microfluidic cell cultures. PLoS ONE 7(5):e37333.
95. Duffy DC, McDonald JC, Schueller OJ, Whitesides GM (1998) Rapid prototyping of microfluidic systems in poly (dimethylsiloxane). Anal Chem 70(23):4974-4984.