Small-molecule inhibitors of the c-Fes protein-tyrosine kinase

Chem Biol. 2012 Apr 20;19(4):529-40. doi: 10.1016/j.chembiol.2012.01.020.


The c-Fes protein-tyrosine kinase modulates cellular signaling pathways governing differentiation, the innate immune response, and vasculogenesis. Here, we report the identification of types I and II kinase inhibitors with potent activity against c-Fes both in vitro and in cell-based assays. One of the most potent inhibitors is the previously described anaplastic lymphoma kinase inhibitor TAE684. The crystal structure of TAE684 in complex with the c-Fes SH2-kinase domain showed excellent shape complementarity with the ATP-binding pocket and a key role for the gatekeeper methionine in the inhibitory mechanism. TAE684 and two pyrazolopyrimidines with nanomolar potency against c-Fes in vitro were used to establish a role for this kinase in osteoclastogenesis, illustrating the value of these inhibitors as tool compounds to probe the diverse biological functions associated with this unique kinase.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Binding Sites
  • COS Cells
  • Cell Differentiation
  • Cell Line
  • Chlorocebus aethiops
  • Computer Simulation
  • Crystallography, X-Ray
  • Mice
  • Microtubules / metabolism
  • Phosphorylation
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins c-fes / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-fes / metabolism
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Signal Transduction / drug effects
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • src Homology Domains


  • NVP-TAE684
  • Pyrimidines
  • Small Molecule Libraries
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-fes