A Structure-Guided Approach to Creating Covalent FGFR Inhibitors
- A Structure-Guided Approach to Creating Covalent FGFR Inhibitors
- Wenjun Zhou; 허우영; Ultan McDermott; Amit Dutt; Wa Xian; Scott B. Ficarro; Jianming Zhang; Sreenath V. Sharma; Joan Brugge; Matthew Meyerson; Jeffrey Settleman; Nathanael S. Gray
- Issue Date
- Chemistry & biology
- VOL 17, NO 3, 285-295
- 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 FGFRdependent 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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