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 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

Fingerprint

Triazines
Calorimetry
src Homology Domains
Surface Plasmon Resonance
Cell Surface Receptors
Inhibitory Concentration 50
Spectrum Analysis
Membrane Proteins
Cell Proliferation
Breast Neoplasms
Binders
Growth
Proteins
Molecules
Cell proliferation
Cell growth
Surface plasmon resonance
Titration
Scaffolds
Assays

Keywords

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

ASJC Scopus subject areas

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

Cite this

Novel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen. / Simister, Philip C.; Luccarelli, James; Thompson, Sam; Appella, Daniel H.; Feller, Stephan M.; Hamilton, Andrew.

In: Bioorganic and Medicinal Chemistry, Vol. 21, No. 14, 15.07.2013, p. 4027-4033.

Research output: Contribution to journalArticle

Simister, Philip C. ; Luccarelli, James ; Thompson, Sam ; Appella, Daniel H. ; Feller, Stephan M. ; Hamilton, Andrew. / Novel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen. In: Bioorganic and Medicinal Chemistry. 2013 ; Vol. 21, No. 14. pp. 4027-4033.
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