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Departments of Pharmacology (D.L.R., J.N.T., R.A.R., R.K.S., J.R.T., R.R.N.) and Internal Medicine (Cardiovascular Medicine) (R.R.N.), and the Center for Chemical Genomics, the University of Michigan Life Sciences Institute (R.R.N.), University of Michigan Medical School, Ann Arbor, Michigan
Regulators of G-protein signaling (RGS) proteins are important components of signal transduction pathways initiated through G-protein-coupled receptors (GPCRs). RGS proteins accelerate the intrinsic GTPase activity of G-protein 
-subunits (G) and thus shorten the time course and reduce the magnitude of G-protein - and 
-subunit signaling. Inhibiting RGS action has been proposed as a means to enhance the activity and specificity of GPCR agonist drugs, but pharmacological targeting of protein-protein interactions has typically been difficult. The aim of this project was to identify inhibitors of RGS4. Using a Luminex 96-well plate bead analyzer and a novel flow-cytometric protein interaction assay to assess G-RGS interactions in a high-throughput screen, we identified the first small-molecule inhibitor of an RGS protein. Of 3028 compounds screened, 1, methyl N-[(4-chlorophenyl)sulfonyl]-4-nitrobenzenesulfinimidoate (CCG-4986), inhibited RGS4/Go binding with 3 to 5 µM potency. It binds to RGS4, inhibits RGS4 stimulation of Go GTPase activity in vitro, and prevents RGS4 regulation of µ-opioid-inhibited adenylyl cyclase activity in permeabilized cells. Furthermore, CCG-4986 is selective for RGS4 and does not inhibit RGS8. Thus, we demonstrate the feasibility of targeting RGS/G protein-protein interactions with small molecules as a novel means to modulate GPCR-mediated signaling processes.
Address correspondence to: Dr. Richard R. Neubig, University of Michigan Medical School, Department of Pharmacology, 1150 W. Medical Center Drive, 1303 MSRB III, Ann Arbor, MI 41809. E-mail: rneubig{at}umich.edu
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