2. Academic Validation
  3. Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

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

  • Proc Natl Acad Sci U S A. 2014 Nov 11;111(45):E4869-77. doi: 10.1073/pnas.1403438111.
Li Tan 1,  Jun Wang 2,  Junko Tanizaki 3,  Zhifeng Huang 4,  Amir R Aref 5,  Maria Rusan 6,  Su-Jie Zhu 7,  Yiyun Zhang 8,  Dalia Ercan 3,  Rachel G Liao 9,  Marzia Capelletti 3,  Wenjun Zhou 1,  Wooyoung Hur 10,  NamDoo Kim 11,  Taebo Sim 12,  Suzanne Gaudet 13,  David A Barbie 2,  Jing-Ruey Joanna Yeh 8,  Cai-Hong Yun 7,  Peter S Hammerman 14,  Moosa Mohammadi 15,  Pasi A Jänne 16,  Nathanael S Gray 17
Affiliations

Affiliations

  • 1 Departments of Biological Chemistry and Molecular Pharmacology, Departments of Cancer Biology and.
  • 2 Medical Oncology.
  • 3 Medical Oncology, The Lowe Center for Thoracic Oncology.
  • 4 Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016; School of Pharmacy, Wenzhou Medical University, Wenzhou, 325035, China;
  • 5 Medical Oncology, Genetics, and.
  • 6 Medical Oncology, Department of Clinical Medicine, Aarhus University, Aarhus, 8200 Denmark;
  • 7 Peking University Health Science Center, Beijing, 100191, China;
  • 8 Medicine, Harvard Medical School, Boston, MA 02115; Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129;
  • 9 Medical Oncology, Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02141;
  • 10 Departments of Biological Chemistry and Molecular Pharmacology, Departments of Cancer Biology and Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, 136-791 Republic of Korea;
  • 11 New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 706-010 Republic of Korea; and.
  • 12 Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, 136-791 Republic of Korea; Korea University-Korean Institute of Science and Technology Graduate School of Converging Science and Technology, Seoul, 136-713 Republic of Korea.
  • 13 Departments of Cancer Biology and Genetics, and Center for Systems Cancer Biology, and.
  • 14 Medical Oncology, Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02141; [email protected] [email protected] [email protected] [email protected].
  • 15 Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016; [email protected] [email protected] [email protected] [email protected].
  • 16 Medical Oncology, The Lowe Center for Thoracic Oncology, Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, MA 02215; [email protected] [email protected] [email protected] [email protected].
  • 17 Departments of Biological Chemistry and Molecular Pharmacology, Departments of Cancer Biology and [email protected] [email protected] [email protected] [email protected].
PMID: 25349422 DOI: 10.1073/pnas.1403438111
Abstract

The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.

Keywords

cancer drug resistance; drug discovery; kinase inhibitor; structure-based drug design.

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