A structure-guided approach to creating covalent FGFR inhibitors

  • Chem Biol. 2010 Mar 26;17(3):285-95. doi: 10.1016/j.chembiol.2010.02.007.
Wenjun Zhou  1 ,  Wooyoung Hur ,  Ultan McDermott ,  Amit Dutt ,  Wa Xian ,  Scott B Ficarro ,  Jianming Zhang ,  Sreenath V Sharma ,  Joan Brugge ,  Matthew Meyerson ,  Jeffrey Settleman ,  Nathanael S Gray
Affiliations
  • 1. Department of Cancer Biology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
PMID: 20338520 DOI: 10.1016/j.chembiol.2010.02.007
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.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15813
    FIIN-1
    99.04%, FGFR Inhibitor
    target: FGFR
    Research Areas: Cancer