A Structure-Guided Approach to Creating Covalent FGFR Inhibitors

Title
A Structure-Guided Approach to Creating Covalent FGFR Inhibitors
Authors
Wenjun Zhou허우영Ultan McDermottAmit DuttWa XianScott B. FicarroJianming ZhangSreenath V. SharmaJoan BruggeMatthew MeyersonJeffrey SettlemanNathanael S. Gray
Issue Date
2010-03
Publisher
Chemistry & biology
Citation
VOL 17, NO 3, 285-295
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 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.
URI
http://pubs.kist.re.kr/handle/201004/49745
ISSN
10745521
Appears in Collections:
KIST Publication > Article
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