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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 Chemistry & biology
Vol 17
Issue 3
Date 2010 Mar 26
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 7 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
FIIN-1 FGFR Inhibitor (Pan) 18 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
ETV6 FGFR1 ETV6 - FGFR1 fusion gain of function - predicted ETV6-FGFR1 results from the fusion of ETV6 (also referred to as TEL) and FGFR1 (PMID: 21764904), and demonstrates transforming ability in cell culture (PMID: 20338520) and therefore, is predicted to confer a gain of function.
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-01-induced growth inhibition in culture (PMID: 20338520). 20338520
FGFR2 K310R FGFR2 N549K endometrial carcinoma sensitive FIIN-1 Preclinical Actionable In a preclinical study, FIIN-01 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-01 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 Actionable In a preclinical study, FIIN-01 inhibited Fgfr1 autophosphorylation in a human transformed embryonic kidney cell line harboring FGFR1 V561M mutation in culture (PMID: 20338520). 20338520
FGFR2 N549K endometrial carcinoma sensitive FIIN-1 Preclinical Actionable In a preclinical study, FIIN-01 inhibited proliferation of endometrial carcinoma cell lines harboring FGFR2 N549K mutation in culture (PMID: 20338520). 20338520
FGFR3 - TACC3 urinary bladder cancer sensitive FIIN-1 Preclinical Actionable In a preclinical study, FIIN-1 inhibited growth of the RT4 bladder cancer cell line, which has been demonstrated to harbor an FGFR3-TACC3 fusion, in culture (PMID: 20338520, PMID: 23175443). 23175443 20338520
FGFR2 amp stomach cancer sensitive FIIN-1 Preclinical Actionable In a preclinical study, FIIN-01 inhibited Fgfr2-dependent cell proliferation of gastric cancer cell lines harboring FGFR2 amplification (PMID: 20338520). 20338520