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

Autor: Simister PC; Biological Systems Architecture Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK., Luccarelli J, Thompson S, Appella DH, Feller SM, Hamilton AD
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2013 Jul 15; Vol. 21 (14), pp. 4027-33. Date of Electronic Publication: 2012 Oct 27.
DOI: 10.1016/j.bmc.2012.10.023
Abstrakt: 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.
(Copyright © 2012 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: