Small Molecule Regulators of Arginine Methyltransferases

描述（由申请人提供）：精氨酸甲基化是一种常见的翻译后修饰，可调节蛋白质功能。精氨酸甲基化的主要蛋白质库具有RNA结合特性。此外，促进组蛋白乙酰化的酶（CBP/p300）和组蛋白本身是精氨酸甲基化的-因此在染色质重塑和转录调控中涉及这种翻译后修饰。在哺乳动物细胞中已经鉴定了七种蛋白质精氨酸N-甲基转移酶（PRMT）：PRMT 1、PRMT 2、PRMTS、PRMT 4/CARM 1、PRMT 5/JBP 1、PRMT 6和PRMT 7。使用化学库和体外实验方法，我们建议开发试点屏幕，以确定小分子，将干扰哺乳动物细胞中的精氨酸甲基化。这些筛选将以这样一种方式进行开发，即它们可以自动化，以便由计划中的NIH资助的HTS筛选中心进行后续的高通量化学筛选（HTS）。PRMT是调节蛋白质相互作用和转录/翻译的新型药物靶标。因此，精氨酸甲基化的小分子调节剂的鉴定将为未来的药物开发提供先导化合物，靶向癌症和可能的其他疾病状态。最重要的是，PRMT是一个新发现的酶家族，尚未被开发为“可药物化”的目标。

DESCRIPTION (provided by applicant): Arginine methylation is a common posttranslational modification that can regulate protein function. The main pool of proteins that are arginine methylated possess RNA binding properties. In addition, enzymes that facilitate histone acetylation (CBP/p300) and histones themselves are arginine methylated - thus implicating this posttranslational modification in chromatin remodeling and transcriptional regulation. Seven protein arginine N-methyltransferases (PRMTs) have been identified in mammalian cells: PRMT1, PRMT2, PRMTS, PRMT4/CARM1, PRMT5/JBP1, PRMT6 and PRMT7. Using a chemical library and in vitro experimental approaches, we propose to develop pilot screens to identify small molecules that will perturb arginine methylation in mammalian cells. The screens will be developed in such a way that they can be automated for subsequent high throughput chemical screening (HTS) by the planned NIH-funded HTS screening centers. The PRMTs are novel drug targets that regulate protein interactions and transcription/translation. Thus, the identification of small molecule regulators of arginine methylation will provide lead compounds for future drug development, targeting cancer and possibly other disease states. Most importantly, the PRMTs are a newly identified family of enzymes that have not yet been tapped as "drugable" targets.