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

Jamie A Moroco1, Matthew P Baumgartner2, Heather L Rust1

  • 1Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Drive, Pittsburgh, PA, 15219, USA.

Chemical Biology & Drug Design
|November 8, 2014
PubMed

Insights

Researchers identified a novel compound, WH-4-124-2, that selectively inhibits the c-Src tyrosine kinase when it interacts with focal adhesion kinase. This discovery offers a targeted approach to blocking tumor cell metastasis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The c-Src tyrosine kinase and focal adhesion kinase (FAK) are crucial in regulating cell adhesion and motility.
  • Their interaction, specifically FAK engaging c-Src's SH3 and SH2 domains, activates c-Src and promotes tumor cell metastasis.

Purpose of the Study:

  • To identify selective inhibitors of the c-Src/FAK complex.
  • To target the specific conformation of c-Src induced by FAK interaction for cancer therapy.

Main Methods:

  • Screening a kinase-biased library using specific assay conditions requiring c-Src binding to a FAK phosphopeptide.
  • Utilizing molecular docking to predict inhibitor binding modes.

Main Results:

  • An aminopyrimidinyl carbamate compound, WH-4-124-2, was identified with nanomolar potency.
  • WH-4-124-2 demonstrated fivefold selectivity for the c-Src/FAK phospho-peptide complex over c-Src alone.
  • Molecular docking suggested WH-4-124-2 preferentially inhibits the 'DFG-out' active site conformation.

Conclusions:

  • The interaction between c-Src and FAK induces a unique kinase domain conformation.
  • This specific conformation is amenable to selective inhibition by compounds like WH-4-124-2.
  • Targeting this interaction offers a potential strategy for inhibiting tumor metastasis.
Keywords:
SH2 domainSH3 domainSrc kinasecancer drug discoveryfocal adhesion kinasekinase inhibitors

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