HTS for Small Molecule Modulators of RGS Proteins

描述(申请人提供)：G蛋白信号(RGS)蛋白的调节器是通过G蛋白偶联受体(GPCRs)启动的重要信号调节器。RGS蛋白的作用是通过调节G？亚单位GTP酶活性，导致信号终止。虽然GPCRs一直是经典的药物靶点，但许多细胞过程可以通过改变RGS蛋白的作用来调节。我建议测量各种RGS蛋白与其效应蛋白(即G？)的相互作用亲和力。使用一种新的高通量流式细胞术方法。在建立了这些参数后，将使用高通量流式细胞术方法筛选不同化合物(~35,000)的库，以识别RGS活性的调节因子。一旦确定了调节剂，将评估完整的定量结构-活性关系，并将在生化和基于细胞的分析中表征更多的类似化合物。这些药理调节剂的使用将为研究RGS蛋白在其中发挥作用的各种疾病提供有用的工具，包括帕金森病(RGS9)、精神分裂症(RGS4)以及细胞增殖和转移(LARG)。

DESCRIPTION (provided by applicant): Regulators of G-protein signaling (RGS) proteins are important modulators of signals initiated through G- protein coupled receptors (GPCRs). The action of RGS proteins is the acceleration of the deactivation of G- protein signals through modulation of G? subunit GTPase activity, which causes a termination of signal. While GPCRs have been classical drug targets, many cellular processes can be modulated by altering the action of RGS proteins. I propose to measure the interaction affinity of a variety of RGS proteins for their effector proteins (i.e. G?) using a novel high throughput flow cytometric method. With these parameters established, a library of diverse chemical compounds (~35,000) will be screened to identify modulators of RGS activity using the high throughput flow cytometric method. Once modulators are identified, complete quantitative structure-activity relationships will be evaluated and additional similar compounds will be characterized in both biochemical and cell-based assays. The use of these pharmacological modulators would provide utility for studying various disease in which RGS proteins could play a role, including Parkinson's disease (RGS9), Schizophrenia (RGS4), as well as cell proliferation and metastasis (LARG).