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).

该项目团队的成员已经确定了代谢酶NNMT在卵巢癌间质中的核心作用。该靶酶在卵巢癌转移的间质中高表达，在原代肿瘤相关成纤维细胞(CAF)中也表达。该酶的敲除会导致CAF的许多特征逆转，并减弱它们在体外和体内促进癌细胞生长的能力。在此期间，项目组成功地优化了一种生化测试，用于筛选100,000多种化合物对NNMT的抑制活性。针对检测的两种成分和三种相关的甲基转移酶进行了反筛选，以筛选出假阳性。几种化学类型被鉴定出具有良好的活性特征，并在体外评估了靶向参与和细胞抑制。得到了其中一种HIT化合物与重组人NNMT的共晶结构，并用于指导药物化学工作。目前正在对选定的HITS进行优化，以提高效力和药代动力学特性。该项目已被NCI实验治疗(NEXT)计划接受，该计划由化学生物学联盟(CBC)管理。