Small molecule inhibitors of regulators of G protein signaling (RGS) proteins

E M Turner; L L Blazer; R R Neubig; Stephen M Husbands

doi:10.1021/ml200263y

Small molecule inhibitors of regulators of G protein signaling (RGS) proteins

E M Turner, L L Blazer, R R Neubig, Stephen M Husbands

Department of Life Sciences

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Abstract

Recently, regulators of G protein signaling (RGS) proteins have emerged as potential therapeutic targets since they provide an alternative method of modulating the activity of G protein-coupled receptors, the target of so many drugs. Inhibitors of RGS proteins must block a protein protein interaction (RGS-G alpha) but also be cell and, depending on the therapeutic target, blood brain barrier permeable. A lead compound (la) was identified as an inhibitor of RGS4 in a screening assay, and this has now been optimized for activity, selectivity, and solubility. The newly developed ligands (11b and 13) display substantial selectivity over the closely related RGS8 protein, lack the off-target calcium mobilization activity of the lead la, and have excellent aqueous solubility. They are currently being evaluated in vivo in rodent models of depression.

Original language	English
Pages (from-to)	146-150
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	3
Issue number	2
Early online date	12 Dec 2011
DOIs	https://doi.org/10.1021/ml200263y
Publication status	Published - 9 Feb 2012

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This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Medicinal Chemistry Letters, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/ml200263y
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Small molecule inhibitors of regulators of G protein signaling (RGS) proteins

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