期刊
CHEMISTRY & BIOLOGY
卷 19, 期 4, 页码 529-540出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2012.01.020
关键词
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资金
- National Institutes of Health [CA123756, GM079575, CA130876]
- Canadian Institutes for Health Research
- Canadian Foundation for Innovation
- Genome Canada through the Ontario Genomics Institute
- GlaxoSmithKline
- Karolinska Institute
- Knut and Alice Wallenberg Foundation
- Ontario Innovation Trust
- Ontario Ministry for Research and Innovation
- Merck Co., Inc.
- Novartis Research Foundation
- Swedish Agency for Innovation Systems
- Swedish Foundation for Strategic Research
- Wellcome Trust
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.
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