Mechanism and Inhibition of Protein Arginine Methylation

蛋白质精氨酸甲基化，其由蛋白质精氨酸甲基转移酶（PRMT）特异性介导， 是生物调节中最重要和最普遍的翻译后修饰之一。 PRMT参与多种细胞过程，包括表观遗传重编程，RNA剪接， 信号转导和DNA修复。大量证据表明，改变的PRMT 表达和活性与肿瘤发生、炎症、糖尿病、神经障碍 以及许多其他的非传染性疾病。PRMTs是一个非常有前途的分子靶点 用于新的化疗然而，PRMT酶在调节信号传导级联和 疾病的传播途径知之甚少。PRMT在主要肿瘤过程中的分子机制 尚未定义。重要的是，优质的化学先导物对于精氨酸的有效靶向作用是稀缺的。 甲基化，这显著阻碍了当前的药物进步。该研究项目旨在 开发新的化学生物学策略和有机探针作为强大的机械手段， 研究PRMT在关键生物学途径和疾病过程中的功能。我们将创新多个 战略设计线，以确定PRMT的底物识别机制，并阐明 表观遗传命运调控中关键组蛋白修饰之间的功能相互作用。我们将努力 致力于开发具有特殊结构的强效和亚型选择性小分子抑制剂， 可用于选择性阻断主要PRMT亚型的酶活性的支架。一 将筛选库化合物的多样性;将合成化学类似物;最好的先导化合物将 表征其药代动力学和药效学性质。详细的生化，细胞， 并将以系统的方式进行体内研究，以确定结构-活性关系， 作用机制，目标是产生新一代有效的亚型选择性PRMT 抑制剂的总之，预计的研究将产生对PRMT调节疾病的深入了解 机制，并将实验室线索转化为临床候选人，用于治疗PRMT相关 疾病

Protein arginine methylation, which is specifically mediated by protein arginine methyltransferases (PRMTs), represents one of the most important and ubiquitous posttranslational modifications in biological regulation. PRMTs are involved in a variety of cellular processes including epigenetic reprograming, RNA splicing, signal transduction, and DNA repair. Significant amounts of evidence have shown that altered PRMT expression and activity are associated with tumorigenesis, inflammation, diabetes, neurological disorders, and many other recalcitrant disease conditions. PRMTs are highly promising molecular targets in the search for new chemotherapies. However, functions of PRMT enzymes in regulating signaling cascades and disease pathways are poorly understood. Molecular mechanisms of PRMTs in major oncology processes are not yet defined. Importantly, quality chemical leads are scarce for effective targeting of arginine methylation, which significantly hampers current pharmaceutical advance. This research project is aimed at developing novel chemical biology strategies and organic probes as powerful mechanistic means to interrogate PRMT function in key biological pathways and disease processes. We will innovate multiple lines of strategic designs to determine substrate recognition mechanisms of PRMTs and illuminate functional interplays among key histone modifications in epigenetic fate regulation. Great efforts will be engaged in developing potent and subtype-selective small molecule inhibitors with privileged structural scaffolds that can be used to selectively block the enzymatic activity of the major PRMT subtypes. A diversity of library compounds will be screened; chemical analogs will be synthesized; and best leads will be characterized for their pharmacokinetics and pharmacodynamics properties. Detailed biochemical, cellular, and in vivo studies will be conducted in a systematic way to define structure-activity relationship and mechanism of action with the goal of generating a new generation of potent, subtype-selective PRMT inhibitors. Altogether, the projected research will yield in-depth understanding of PRMT-regulated disease mechanisms and translate laboratory leads into clinical candidates for the treatment of PRMT-related ailments.