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A structure-guided approach to creating covalent FGFR inhibitors.

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 (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.

SUBMITTER: Zhou W

PROVIDER: S-EPMC2920453 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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A structure-guided approach to creating covalent FGFR inhibitors.

Zhou Wenjun W Hur Wooyoung W McDermott Ultan U Dutt Amit A Xian Wa W Ficarro Scott B SB Zhang Jianming J Sharma Sreenath V SV Brugge Joan J Meyerson Matthew M Settleman Jeffrey J Gray Nathanael S NS

Chemistry & biology 20100301 3

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 ...[more]

PMID: 20338520

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