Author/Authors :
Sabine Hellwig، نويسنده , , Chandra V. Miduturu، نويسنده , , Shigeru Kanda، نويسنده , , Jianming Zhang، نويسنده , , Panagis Filippakopoulos، نويسنده , , Eidarus Salah، نويسنده , , Xianming Deng، نويسنده , , Hwan Geun Choi، نويسنده , , Wenjun Zhou، نويسنده , , Wooyoung Hur، نويسنده , , Stefan Knapp، نويسنده , , Nathanael S. Gray، نويسنده , , Thomas E. Smithgall، نويسنده ,
Abstract :
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.
