Cell-based Screen for RGS Modulators

描述(申请人提供)：信号转导过程是药物发现的主要目标，G蛋白偶联受体是许多当前治疗药物的主要作用部位。然而，最近的工作表明，信号通路不仅是线性信息链，而且是相互作用的调控分子的网络，其中蛋白质支架、细胞内接近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蛋白信号转导的20个G蛋白信号调节蛋白(RGS)家族成员是药物干预的新靶点，但它们的生理功能仍不完全清楚，RGS功能的小分子抑制剂尚未见报道。选择性RGS抑制剂的鉴定将提供：1)研究RGS在细胞和体内的功能的工具；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。该项目的最终目标是鉴定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。 与公共健康相关：目前，许多商业药物开发的目标是人类基因组的一小部分，被认为是“可用药的”。在目前的项目中，我们正在识别作用于一个新的基因家族的化学物质，这些基因在控制大脑功能方面发挥关键作用--G蛋白信号的调节。最近的研究表明，这些蛋白质与抑郁症、精神分裂症、癫痫和其他疾病有关。通过抑制或增强RGS蛋白的功能，我们的长期目标是开发新的药物，以改善这些疾病的治疗。

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.