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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.

Author information

1
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Drive, Pittsburgh, PA, 15219, USA.
2
Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, 3501 Fifth Avenue, Pittsburgh, PA, 15260, USA.
3
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , 250 Longwood Avenue, Boston, MA, 02115, USA.
4
Department of Cancer Biology, Dana-Farber Cancer Institute, 250 Longwood Avenue, Boston, MA, 02115, USA.

Abstract

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.

KEYWORDS:

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

PMID:
25376742
PMCID:
PMC4444405
DOI:
10.1111/cbdd.12473
[Indexed for MEDLINE]
Free PMC Article

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