HTS for Small Molecule Modulators of RGS Proteins

描述（由申请人提供）：G蛋白信号传导（RGS）蛋白的调节剂是通过G蛋白偶联受体（gpcr）启动的信号的重要调节剂。RGS蛋白的作用是通过调节G?加速G蛋白信号的失活。亚基GTPase活性，导致信号终止。虽然gpcr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。我建议使用一种新的高通量流式细胞术方法来测量各种RGS蛋白与其效应蛋白（即G?）的相互作用亲和力。建立这些参数后，将使用高通量流式细胞术筛选不同化合物库（~35,000），以确定RGS活性的调节剂。一旦确定了调节剂，将评估完整的定量结构-活性关系，并在生化和基于细胞的分析中对其他类似化合物进行表征。这些药理调节剂的使用将为研究RGS蛋白可能发挥作用的各种疾病提供实用工具，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).