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.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cysteine / metabolism
  • Humans
  • Models, Molecular
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Receptors, Fibroblast Growth Factor / antagonists & inhibitors*
  • Receptors, Fibroblast Growth Factor / chemistry
  • Receptors, Fibroblast Growth Factor / metabolism
  • Signal Transduction

Substances

  • Protein Kinase Inhibitors
  • Pyrimidines
  • Receptors, Fibroblast Growth Factor
  • Cysteine