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- 题目:
- Identification of small-molecule inhibitors of RGS4 using a high-throughput flow cytometry protein interaction assay.
- 作者:
- Roman(David L),Talbot(Jeffery N),Roof(Rebecca A),Sunahara(Roger K),Traynor(John R),Neubig(Richard R)
- 状态:
- 发布时间2006-12-22 , 更新时间 2007-12-03
- 期刊:
- Mol Pharmacol
- 摘要:
- 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 alpha-subunits (Galpha) and thus shorten the time course and reduce the magnitude of G-protein alpha- and betagamma-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 Galpha-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/Galpha(o) binding with 3 to 5 muM potency. It binds to RGS4, inhibits RGS4 stimulation of Galpha(o) GTPase activity in vitro, and prevents RGS4 regulation of mu-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/Galpha protein-protein interactions with small molecules as a novel means to modulate GPCR-mediated signaling processes.
- 语言:
- eng
- DOI:
- 10.1124/mol.106.028670
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