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Ref Type Journal Article
PMID (25349422)
Authors Tan L, Wang J, Tanizaki J, Huang Z, Aref AR, Rusan M, Zhu SJ, Zhang Y, Ercan D, Liao RG, Capelletti M, Zhou W, Hur W, Kim N, Sim T, Gaudet S, Barbie DA, Yeh JR, Yun CH, Hammerman PS, Mohammadi M, Jänne PA, Gray NS
Title Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors.
Abstract Text 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.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
FIIN-2 FIIN-2 7 0
FIIN-3 FIIN-3 3 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
FIIN-2 FIIN 2|FIIN2 FGFR Inhibitor (Pan) 25 FIIN-2 is a selective, irreversible Fgfr inhibitor with activity against Fgfr mutations that confer resistance to first-generation Fgfr inhibitors, potentially resulting in decreased tumor cell proliferation (PMID: 25349422).
FIIN-3 FIIN3|FIIN 3 FGFR Inhibitor (Pan) 25 FIIN-3 is a selective, irreversible FGFR inhibitor with activity against FGFR2 gatekeeper mutations, which potentially results in decreased tumor cell proliferation (PMID: 25349422, PMID: 32723837).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR2 V564M missense unknown FGFR2 V564M lies within the protein kinase domain of the Fgfr2 protein ( V564M has been demonstrated to confer resistance to Fgfr inhibitors in culture (PMID: 25349422), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Nov 2023). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 V564M Advanced Solid Tumor resistant Infigratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FGFR2 V564M were resistant to Truseltiq (infigratinib) in culture (PMID: 25349422). 25349422
FGFR2 V564F Advanced Solid Tumor resistant Infigratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FGFR2 V564F were resistant to Truseltiq (infigratinib) in culture (PMID: 25349422). 25349422