title: Novel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen.
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.
authors.affiliation: Biological Systems Architecture Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Simister
authors.forename: James
authors.initials: J
authors.lastname: Luccarelli
authors.forename: Sam
authors.initials: S
authors.lastname: Thompson
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Appella
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Feller
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hamilton
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors*; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490895:GAB2 protein, human; D054852:Small Molecule Libraries