期刊
CHEMISTRY & BIOLOGY
卷 17, 期 3, 页码 285-295出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2010.02.007
关键词
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资金
- Damon Runyon Cancer Foundation
- Mary Kay Ash Foundation
- National Science Foundation
- Directorate For Engineering
- Div Of Chem, Bioeng, Env, & Transp Sys [0744413] Funding Source: National Science Foundation
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.
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