qHTS to Identify Inhibitors of NNMT1

qHTS 鉴定 NNMT1 抑制剂

• 批准号: 10000751
• 负责人: Matthew Hall
• 金额: $ 25.03万
• 依托单位: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10000751
• 关键词: Attenuated; Biochemical; Biological Assay; Biology; Cancer Cell Growth; Cancer Etiology; Cessation of life; Chemicals; Crystallization; Disease; Enzymes; Female Genital Neoplasms; Fibroblasts; Greater sac of peritoneum; Human; In Vitro; Investigational Therapies; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Metabolic; Methyltransferase; Mutation; Neoplasm Metastasis; Nicotinamide N-Methyltransferase; Ovary; Pathway interactions; Patients; Pharmaceutical Chemistry; Property; Quality of life; Recombinants; Recurrence; Role; Serous; Site; Structure; Symptoms; TP53 gene; Treatment Efficacy; Woman; improved; in vivo; inhibitor/antagonist; knock-down; member; mortality; outcome forecast; programs; tumor; tumor heterogeneity

Members of the project team have identified a central role of the metabolic enzyme NNMT in the stroma of ovarian cancer. The target enzyme is highly expressed in the stroma of ovarian cancer metastases and is also expressed in primary cancer-associated fibroblasts (CAFs). Knockdown of the enzyme leads to a reversion of many of the features of CAFs and attenuates their ability to promote cancer cell growth both in vitro and in vivo. During this period, the project team successfully optimized a biochemical assay that was used to screen over 100,000 compounds for inhibitory activity against NNMT. Counter-screens against two components of the assay, and three related methyltransferase enzymes, were performed to filter out the false positives. Several chemotypes were identified with favorable activity profiles, and in vitro target engagement and cellular inhibition were assessed. Co-crystal structure of one of the hit compounds with recombinant human NNMT has been obtained and been used to guide the medicinal chemistry efforts. Optimization of selected hits is currently underway to improve potency and pharmacokinectic properties. The project has been accepted by the NCI Experimental Therapeutics (NExT) program under the management of Chemical Biology Consortium (CBC).

项目小组的成员确定了代谢酶NNMT在卵巢癌基质中的核心作用。靶酶在卵巢癌转移的基质中高度表达，并且在原发性癌症相关的成纤维细胞（CAF）中也表达。酶的敲低酶导致了CAF的许多特征的恢复，并减弱了它们在体外和体内促进癌细胞生长的能力。在此期间，项目团队成功地优化了一种生化测定，该测定法用于筛选超过100,000种对NNMT的抑制活性。对测定的两个组成部分和三个相关的甲基转移酶进行了反屏幕，以滤除误报。鉴定了几种化学型，具有有利的活性谱，并评估了体外靶标参与和细胞抑制作用。已经获得了重组人NNMT的一种热门化合物的共晶结构，并用于指导药物化学工作。目前正在进行优化选定的命中以提高效力和药代动力学特性。该项目已被化学生物联盟管理（CBC）管理下的NCI实验疗法（下一个）计划接受。