Small Molecule Regulators of Arginine Methyltransferases

精氨酸甲基转移酶的小分子调节剂

基本信息

批准号：
6905299
负责人：
MARK T. BEDFORD
金额：
$ 22.73万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2008-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6905299
关键词：
HeLa cells arginine biotechnology chemical genetics chimeric proteins clinical research drug discovery /isolation enzyme activity enzyme inhibitors enzyme linked immunosorbent assay high throughput technology methylation methyltransferase monoclonal antibody posttranslational modifications recombinant proteins small molecule technology /technique development

项目摘要

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.

描述（申请人提供）：精氨酸甲基化是一种常见的翻译后修饰，可以调节蛋白质功能。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 (CBP/p300) 的酶和组蛋白本身被精氨酸甲基化，因此暗示染色质重塑和转录调控中的这种翻译后修饰。在哺乳动物细胞中已鉴定出七种蛋白质精氨酸 N-甲基转移酶 (PRMT)：PRMT1、PRMT2、PRMTS、PRMT4/CARM1、PRMT5/JBP1、PRMT6 和 PRMT7。使用化学库和体外实验方法，我们建议开发试点筛选来识别会扰乱哺乳动物细胞中精氨酸甲基化的小分子。这些筛选的开发方式将使其能够自动化，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/翻译的新型药物靶点。因此，精氨酸甲基化小分子调节剂的鉴定将为未来针对癌症和可能的其他疾病状态的药物开发提供先导化合物。最重要的是，PRMT 是一个新发现的酶家族，尚未被开发为“可成药”靶标。