Author/Authors :
Wenjun Zhou، نويسنده , , Wooyoung Hur، نويسنده , , Ultan McDermott، نويسنده , , Amit Dutt، نويسنده , , Wa Xian، نويسنده , , Scott B. Ficarro، نويسنده , , Jianming Zhang، نويسنده , , Sreenath V. Sharma، نويسنده , , Joan Brugge، نويسنده , , Matthew Meyerson، نويسنده , , Jeffrey Settleman، نويسنده , , Nathanael S. Gray، نويسنده ,
Abstract :
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 (EC50 = 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.
