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

Bioorg Med Chem. 2013 Jul 15;21(14):4027-33. doi: 10.1016/j.bmc.2012.10.023. Epub 2012 Oct 27.

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 310 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 320μM). 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
  • Humans
  • Hydrogen Bonding
  • Inhibitory Concentration 50
  • Models, Molecular
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • src Homology Domains*

Substances

  • Adaptor Proteins, Signal Transducing
  • GAB2 protein, human
  • Small Molecule Libraries