Reference Detail

Ref Type

Journal Article

PMID

(20338520)

Authors

Zhou W, Hur W, McDermott U, Dutt A, Xian W, Ficarro SB, Zhang J, Sharma SV, Brugge J, Meyerson M, Settleman J, Gray NS

Title

A structure-guided approach to creating covalent FGFR inhibitors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Chemistry & biology	17	3	2010 Mar 26	285-95	Chem Biol

URL

Abstract Text

The fibroblast growth factor receptor tyrosine kinases (FGFR1, 2, 3, and 4) represent promising therapeutic targets in a number of cancers. We have developed the first potent and selective irreversible inhibitor of FGFR1, 2, 3, and 4, which we named FIIN-1 that forms a covalent bond with cysteine 486 located in the P loop of the FGFR1 ATP binding site. We demonstrated that the inhibitor potently inhibits Tel-FGFR1-transformed Ba/F3 cells (EC(50) = 14 nM) as well as numerous FGFR-dependent cancer cell lines. A biotin-derivatized version of the inhibitor, FIIN-1-biotin, was shown to covalently label FGFR1 at Cys486. FIIN-1 is a useful probe of FGFR-dependent cellular phenomena and may provide a starting point of the development of therapeutically relevant irreversible inhibitors of wild-type and drug-resistant forms of FGFR kinases.

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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-1	FIIN-1	6	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
FIIN-1			FGFR Inhibitor (Pan) 26	FIIN-1 is an irreversible pan-FGFR inhibitor which blocks activation and downstream signaling and may inhibit transformation and proliferation in cancer cells (PMID: 20338520).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR2 wild-type	endometrial carcinoma	resistant	FIIN-1	Preclinical	Actionable	In a preclinical study, an endometrial carcinoma cell line harboring wild-type FGFR2 was resistant to FIIN-1-induced growth inhibition in culture (PMID: 20338520).	20338520
FGFR2 N549K	endometrial carcinoma	sensitive	FIIN-1	Preclinical	Actionable	In a preclinical study, FIIN-1 inhibited proliferation of endometrial carcinoma cell lines harboring FGFR2 N549K mutation in culture (PMID: 20338520).	20338520
FGFR2 amp	stomach cancer	sensitive	FIIN-1	Preclinical	Actionable	In a preclinical study, FIIN-1 inhibited Fgfr2-dependent cell proliferation of gastric cancer cell lines harboring FGFR2 amplification (PMID: 20338520).	20338520
FGFR2 K310R FGFR2 N549K	endometrial carcinoma	sensitive	FIIN-1	Preclinical	Actionable	In a preclinical study, FIIN-1 inhibited proliferation of endometrial carcinoma cell lines harboring FGFR2 N549K and FGFR2 K310R mutations in culture (PMID: 20338520).	20338520
FGFR1 act mut	breast cancer	sensitive	FIIN-1	Preclinical	Actionable	In a preclinical study, FIIN-1 inhibited Fgfr1 activation-induced proliferation and transformation of human breast epithelial cell lines in culture (PMID: 20338520).	20338520
FGFR1 V561M	Advanced Solid Tumor	sensitive	FIIN-1	Preclinical - Biochemical	Actionable	In a preclinical study, FIIN-1 inhibited Fgfr1 autophosphorylation in a human transformed embryonic kidney cell line harboring FGFR1 V561M mutation in culture (PMID: 20338520).	20338520