Cell-based Screen for RGS Modulators

描述（由申请人提供）：信号转导过程是药物发现的主要靶点，G蛋白偶联受体是许多当前治疗剂的主要作用位点。然而，最近的研究表明，信号通路不仅仅是线性的信息链，而是相互作用的调节分子的网络，其中蛋白质支架、细胞内接近性和抑制控制是信号有效性和特异性的主要决定因素。抑制G蛋白信号的20个G蛋白信号调节因子（RGS）蛋白家族成员代表了一个新的药物干预位点，但是：1)它们的生理功能仍然不完全清楚；2)没有报道的RGS功能的小分子抑制剂。选择性RGS抑制剂的鉴定将提供：1)研究RGS在细胞和体内功能的工具；2)治疗药物开发的起点。我们最近开发了一种强大的基于细胞的功能分析来评估RGS4的活性。这将用于MLPCN的高通量筛选，以确定选择性抑制RGS4活性的化合物。本项目的最终目的是鉴定RGS作用的选择性小分子调节剂。这将提供重要的化学工具并加速新疗法的发展。

DESCRIPTION (provided by applicant): Signal transduction processes are major targets of drug discovery with G protein-coupled receptors being a primary site of action of many current therapeutic agents. Recent work, however, has shown that signaling pathways are not just linear chains of information but are webs of interacting regulatory molecules in which protein scaffolding, intracellular proximity, and inhibitory control are major determinants of signaling efficacy and specificity. The twenty Regulator of G protein Signaling (RGS) protein family members which inhibit G protein signaling represent a novel site of pharmacologic intervention but: 1) their physiological functions remain incompletely understood and 2) there are no reported small molecule inhibitors of RGS function. The identification of selective RGS inhibitors would provide both: 1) tools for the study of RGS function in cells and in vivo and 2) a starting point for therapeutic drug development. We have recently developed a robust cell- based functional assay for assessing RGS4 activity. This will be utilized in high-throughput screening in the MLPCN to identify compounds that selectively inhibit the activity of RGS4. The ultimate aim of this project is the identification of selective small molecule modulators of RGS action. This will provide important chemical tools and accelerate the development of novel therapeutics. PUBLIC HEALTH RELEVANCE: Much of commercial drug development currently targets a small subset of the human genome which is considered "druggable". In the present project, we are identifying chemicals that act on a new family of genes that play a key role in controlling brain function - the regulators of G protein signaling. Recent work implicates these proteins in depression, schizophrenia, epilepsy, and other disorders. By inhibiting or enhancing the function of RGS proteins, our long term goal is to develop novel drugs that will improve therapy of these conditions.