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部位。然而，最近的工作表明，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，细胞内邻近和抑制控制是信号功效和特异性的主要决定因素。抑制G蛋白信号传导的20种G蛋白信号传导调节剂（Regulator of G protein Signaling，RGS）蛋白家族成员代表了药理学干预的新位点，但是：1）它们的生理功能仍然不完全理解，2）没有报道RGS功能的小分子抑制剂。选择性RGS抑制剂的鉴定将提供：1）用于研究细胞和体内RGS功能的工具和2）治疗药物开发的起点。我们最近开发了一种用于评估RGS 4活性的稳健的基于细胞的功能测定。这将用于MLPCN中的高通量筛选，以鉴定选择性抑制RGS 4活性的化合物。该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，并加速新疗法的开发。 公共卫生相关性：目前大部分商业药物开发针对人类基因组的一小部分，这被认为是“可药用的”。在目前的项目中，我们正在确定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中起着关键作用-G蛋白信号的调节剂。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，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.