Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Proceedings of the National Academy of Sciences of the United States of America	111	45	2014 Nov 11	E4869-77	Proc Natl Acad Sci U S A

URL

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) 26	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) 26	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 (UniProt.org). 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 2024).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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
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