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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.

Original publication

DOI

10.1016/j.chembiol.2012.01.020

Type

Journal article

Journal

Chem Biol

Publication Date

20/04/2012

Volume

19

Pages

529 - 540

Keywords

Animals, Binding Sites, COS Cells, Cell Differentiation, Cell Line, Cercopithecus aethiops, Computer Simulation, Crystallography, X-Ray, Mice, Microtubules, Phosphorylation, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-fes, Pyrimidines, Signal Transduction, Small Molecule Libraries, src Homology Domains