Department of Pharmacology, UNC Neuroscience Center, UNC School of Medicine, University of North Carolina at Chapel Hill, 120 Mason Farm Road, Suite 4010, Chapel Hill, NC 27599-7365, USA.
Pharmacol Rev. 2011 Sep;63(3):728-49. doi: 10.1124/pr.110.003038. Epub 2011 Jul 7.
Because G-protein coupled receptors (GPCRs) continue to represent excellent targets for the discovery and development of small-molecule therapeutics, it is posited that additional protein components of the signal transduction pathways emanating from activated GPCRs themselves are attractive as drug discovery targets. This review considers the drug discovery potential of two such components: members of the "regulators of G-protein signaling" (RGS protein) superfamily, as well as their substrates, the heterotrimeric G-protein α subunits. Highlighted are recent advances, stemming from mouse knockout studies and the use of "RGS-insensitivity" and fast-hydrolysis mutations to Gα, in our understanding of how RGS proteins selectively act in (patho)physiologic conditions controlled by GPCR signaling and how they act on the nucleotide cycling of heterotrimeric G-proteins in shaping the kinetics and sensitivity of GPCR signaling. Progress is documented regarding recent activities along the path to devising screening assays and chemical probes for the RGS protein target, not only in pursuits of inhibitors of RGS domain-mediated acceleration of Gα GTP hydrolysis but also to embrace the potential of finding allosteric activators of this RGS protein action. The review concludes in considering the Gα subunit itself as a drug target, as brought to focus by recent reports of activating mutations to GNAQ and GNA11 in ocular (uveal) melanoma. We consider the likelihood of several strategies for antagonizing the function of these oncogene alleles and their gene products, including the use of RGS proteins with Gα(q) selectivity.
由于 G 蛋白偶联受体 (GPCR) 仍然是发现和开发小分子治疗药物的极佳靶点，因此推测源自激活的 GPCR 本身的信号转导途径的其他蛋白质成分作为药物发现靶点具有吸引力。这篇综述考虑了两种此类成分的药物发现潜力：“G 蛋白信号转导调节剂”(RGS 蛋白) 超家族的成员，以及它们的底物，异三聚体 G 蛋白 α 亚基。突出显示的是最近的进展，源自小鼠敲除研究以及使用“RGS 不敏感”和快速水解突变对 Gα 的研究，这些进展使我们对 RGS 蛋白如何在受 GPCR 信号控制的 (病理)生理条件下选择性发挥作用以及它们如何作用于异三聚体 G 蛋白的核苷酸循环来塑造 GPCR 信号的动力学和敏感性有了更好的理解。在设计用于 RGS 蛋白靶标的筛选测定和化学探针的过程中，记录了沿着这条道路取得的进展，不仅是为了寻找 RGS 结构域介导的 Gα GTP 水解加速的抑制剂，而且还为发现这种 RGS 蛋白作用的别构激活剂的潜力做好准备。综述以最近报道的眼 (葡萄膜) 黑素瘤中 GNAQ 和 GNA11 的激活突变为焦点，考虑了将 Gα 亚基本身作为药物靶标的可能性。我们考虑了几种拮抗这些致癌基因等位基因及其基因产物功能的策略的可能性，包括使用具有 Gα(q) 选择性的 RGS 蛋白。
