Novel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen

Philip C. Simister, James Luccarelli, Sam Thompson, Daniel H. Appella, Stephan M. Feller, Andrew D. Hamilton

Research output: Contribution to journalArticle

Abstract

The adaptor protein Grb2 links cell-surface receptors, such as Her2, to the multisite docking proteins Gab1 and 2, leading to cell growth and proliferation in breast and other cancers. Gab2 interacts with the C-terminal SH3 domain (SH3C) of Grb2 through atypical RxxK motifs within polyproline II or 3 10 helices. A virtual screen was conducted for putative binders of the Grb2 SH3C domain. Of the top hits, 34 were validated experimentally by surface plasmon resonance spectroscopy and isothermal titration calorimetry. A subset of these molecules was found to inhibit the Grb2-Gab2 interaction in a competition assay, with moderate to low affinities (5: IC50 320 μM). The most promising binders were based on a dihydro-s-triazine scaffold, and are the first small molecules reported to target the Grb2 SH3C protein-interaction surface.

Original languageEnglish (US)
Pages (from-to)4027-4033
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number14
DOIs
StatePublished - Jul 15 2013

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Keywords

  • Gab2
  • Grb2
  • Inhibitors
  • Protein-protein interaction
  • SH3 Domain
  • Virtual screening

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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