Discovery of small molecule inhibitors for protein N-terminal methyltransferase

新的证据表明，蛋白质甲基转移酶(PMT)起着至关重要的作用 在不同的生物过程和包括癌症在内的各种人类疾病中。蛋白质N端 甲基转移酶1(NTMT1/NRMT1)在细胞分裂、DNA修复和 染色质相互作用。NTMT1在多种癌症患者组织中表达上调，其过度表达与肿瘤的发生、发展密切相关。 在结直肠腺癌和结直肠癌中的表达水平均排在前1% 黑色素瘤。此外，NTMT1的缺失会导致癌细胞有丝分裂缺陷，并使 从DNA到化疗药物。因此，NTMT1是一个引人注目的开发目标 治疗结直肠癌和黑色素瘤的新癌症疗法。因此，感兴趣的是 开发可用作生物探针和铅的新型小分子抑制剂 用于药物开发的分子。然而，目前还没有专门的小分子探针。 可用于NTMT1，以提供对NTMT1甲基转移酶功能的新见解 肿瘤发生中的活动性。为了填补这一空白，我们的长期目标是发现新颖、有效和 选择性小分子NTMT1抑制剂。对于这个应用程序，我们将开发一系列简单的 和可重复的高通量筛查(HTS)分析，并运行试点筛查，包括 大约15,000种化合物与国家研究中心合作验证这些检测 先进翻译科学化学基因组学中心(NCGC)。在目标1中，我们将 建立一次、二次和二次HTS兼容的生化NTMT1检测 定量HTS格式。在目标2中，我们将与选定的图书馆进行试点研究，以确定 NTMT1的小分子抑制剂。在目标3中，我们将在 结构、选择性和基于细胞的研究。 在这个项目完成后，我们希望定义生化和基于细胞的分析 筛选大的小分子文库，以确定NTMT1的有效和选择性抑制剂。 我们预计，这些研究将导致确定有效和选择性的First in-in- NTMT1类小分子抑制剂，用于进一步开发作为化学探针。这个 所获得的知识将加速NTMT1调制器和我们的 癌症患者对NTMT1调控通路的理解。NCGC的顶级放映 该计划和我们在药物发现方面的经验整合了成功所需的专业知识 在这样的努力中。

Emerging evidence implies that protein methyltransferases (PMTs) that play a crucial role in diverse biological processes and various human dieases including cancer. Protein N-terminal methyltransferase 1 (NTMT1/NRMT1) plays an important role in cell division, DNA repair, and chromatin interaction. NTMT1 is upregulated in various cancer patients' tissues, and its over- expression level ranks in the top 1% in both colorectal adenocarcinoma and malignant melanoma. Moreover, loss of NTMT1 results in cancer cell mitotic defects and sensitizes the DNA to chemotherapeutic agents. Therefore, NTMT1 is a compelling target for development of novel cancer therapeutics for colorectal cancer and melanoma. Therefore, it is of interest to develop novel small molecule inhibitors that might serve as biological probes as well as lead molecules for drug development. However, there are no specific small molecule probes available for NTMT1 to provide new insights into the functions of NTMT1 methyltransferase activity in tumorigenesis. To fill this gap, our long-term goal is to discover of novel, potent, and selective small molecule NTMT1 inhibitors. For this application, we will develop a series of facile and reproducible high-throughput screening (HTS) assays and run a pilot screen comprised of about 15,000 compounds to validate these assays in collaboration with the National Center for Advancing Translational Sciences Chemical Genomics Center (NCGC). In Aim 1, we will develop primary, counter, and secondary HTS-compatible biochemical NTMT1 assays in a quantitative HTS format. In Aim 2, we will perform pilot studies with selected libraries to identify small molecule inhibitors for NTMT1. In aim 3, we will characterize active compounds in structural, selectivity, and cell-based studies. Upon completion of this project we expect to define biochemical and cell based assays to screen large libraries of small molecules to identify potent and selective inhibitors of NTMT1. We anticipate that these studies will result in the identification of potent and selective first-in- class NTMT1 small molecule inhibitors for further development as chemical probes. The knowledge gained would expedite the development of NTMT1 modulators and our understanding of NTMT1-regulated pathways in cancer patients. The NCGC's top tier screening program and our experience in drug discovery integrate the expertise needed to be successful in such endeavor.