title: Small-molecule inhibitors of the c-Fes protein-tyrosine kinase.
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.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hellwig
authors.forename: Chandra V
authors.initials: CV
authors.lastname: Miduturu
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kanda
authors.forename: Jianming
authors.initials: J
authors.lastname: Zhang
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.forename: Eidarus
authors.initials: E
authors.lastname: Salah
authors.forename: Xianming
authors.initials: X
authors.lastname: Deng
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhou
authors.forename: Wooyoung
authors.initials: W
authors.lastname: Hur
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Smithgall
mesh_terms: D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002454:Cell Differentiation; D002460:Cell Line; D002522:Chlorocebus aethiops; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051578:Proto-Oncogene Proteins c-fes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D018909:src Homology Domains
chemical_list: C516714:NVP-TAE684; D011743:Pyrimidines; D054852:Small Molecule Libraries; D011505:Protein-Tyrosine Kinases; D051578:Proto-Oncogene Proteins c-fes