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Chem Biol Drug Des. 2015 Aug;86(2):144-55. doi: 10.1111/cbdd.12473. Epub 2014 Nov 28.

A Discovery Strategy for Selective Inhibitors of c-Src in Complex with the Focal Adhesion Kinase SH3/SH2-binding Region.

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Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Drive, Pittsburgh, PA, 15219, USA.
Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, 3501 Fifth Avenue, Pittsburgh, PA, 15260, USA.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , 250 Longwood Avenue, Boston, MA, 02115, USA.
Department of Cancer Biology, Dana-Farber Cancer Institute, 250 Longwood Avenue, Boston, MA, 02115, USA.


The c-Src tyrosine kinase co-operates with the focal adhesion kinase to regulate cell adhesion and motility. Focal adhesion kinase engages the regulatory SH3 and SH2 domains of c-Src, resulting in localized kinase activation that contributes to tumor cell metastasis. Using assay conditions where c-Src kinase activity required binding to a tyrosine phosphopeptide based on the focal adhesion kinase SH3-SH2 docking sequence, we screened a kinase-biased library for selective inhibitors of the Src/focal adhesion kinase peptide complex versus c-Src alone. This approach identified an aminopyrimidinyl carbamate compound, WH-4-124-2, with nanomolar inhibitory potency and fivefold selectivity for c-Src when bound to the phospho-focal adhesion kinase peptide. Molecular docking studies indicate that WH-4-124-2 may preferentially inhibit the 'DFG-out' conformation of the kinase active site. These findings suggest that interaction of c-Src with focal adhesion kinase induces a unique kinase domain conformation amenable to selective inhibition.


SH2 domain; SH3 domain; Src kinase; cancer drug discovery; focal adhesion kinase; kinase inhibitors

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