Reversible, allosteric small-molecule inhibitors of regulator of G protein signaling proteins

Reference:

Blazer, L. L., Roman, D. L., Chung, A., Larsen, M. J., Greedy, B. M., Husbands, S. M. and Neubig, R. R., 2010. Reversible, allosteric small-molecule inhibitors of regulator of G protein signaling proteins. Molecular Pharmacology, 78 (3), pp. 524-533.

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Official URL:

http://dx.doi.org/10.1124/mol.110.065128

Abstract

Regulators of G protein signaling (RGS) proteins are potent negative modulators of G protein signaling and have been proposed as potential targets for small-molecule inhibitor development. We report a high-throughput time-resolved fluorescence resonance energy transfer screen to identify inhibitors of RGS4 and describe the first reversible small-molecule inhibitors of an RGS protein. Two closely related compounds, typified by CCG-63802 [((2E)-2-(1,3-benzothiazol-2-yl)-3-[9-methyl-2-(3-methylphenoxy)-4-oxo-4 H-pyrido[1,2-a]pyrimidin-3-yl]prop-2-enenitrile)], inhibit the interaction between RGS4 and G alpha(o) with an IC50 value in the low micromolar range. They show selectivity among RGS proteins with a potency order of RGS 4 > 19 = 16 > 8 >> 7. The compounds inhibit the GTPase accelerating protein activity of RGS4, and thermal stability studies demonstrate binding to the RGS but not to G alpha(o). On RGS4, they depend on an interaction with one or more cysteines in a pocket that has previously been identified as an allosteric site for RGS regulation by acidic phospholipids. Unlike previous small-molecule RGS inhibitors identified to date, these compounds retain substantial activity under reducing conditions and are fully reversible on the 10-min time scale. CCG-63802 and related analogs represent a useful step toward the development of chemical tools for the study of RGS physiology.

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