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|Ref Type||Journal Article|
|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|
|Date||2010 Mar 26|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|FIIN-1||FGFR Inhibitor (Pan) 24||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 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|
|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|
|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|
|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|
|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 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|