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

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...

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Bibliographic Details
Main Authors: Simister, P, Luccarelli, J, Thompson, S, Appella, D, Feller, S, Hamilton, A
Format: Journal article
Language:English
Published: 2013
Description
Summary: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.