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qHTS to Identify Inhibitors of NNMT1

qHTS 鉴定 NNMT1 抑制剂

基本信息

批准号：
10255295
负责人：
Matthew Hall
金额：
$ 30.57万
依托单位：
NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
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/10255295
关键词：
Animal Cancer Model Attenuated Biochemical Biological Assay Biology Cancer Cell Growth Cancer Etiology Cessation of life Chemicals Crystallization Disease Dose Drug Kinetics Enzymes Female Genital Neoplasms Fibroblasts Future Greater sac of peritoneum Human In Vitro Investigational Therapies Malignant Neoplasms Malignant neoplasm of ovary Mammalian Oviducts Metabolic Methyltransferase Modeling Mus Mutation Neoplasm Metastasis Nicotinamide N-Methyltransferase Ovary Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Property Quality of life Recombinants Recurrence Role Serous Site Structure Symptoms TP53 gene Treatment Efficacy Woman analog experimental study improved in vivo inhibitor/antagonist knock-down member mortality outcome forecast programs standard of care tumor tumor heterogeneity

项目摘要

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 structures of a number of hit compounds with recombinant human NNMT have been obtained and been used to guide the medicinal chemistry efforts. After the project was accepted by the NCI Experimental Therapeutics (NExT) program under the management of Chemical Biology Consortium (CBC), four potent and selective triazolone analogs with attractive drug-like properties have been characterized in single-dose mouse pharmacokinetic-pharmacodynamic experiments and two compounds are being progressed towards proof-of-concept efficacy experiments in an ovarian cancer animal model. Ongoing and future activities will focus on the further characterization in multiple efficacy and survival models of both these compounds and future analogs in combination with the standard of care treatment for ovarian cancer.

该项目组的成员已经确定了代谢酶NNMT在卵巢癌间质中的核心作用。靶酶在卵巢癌转移的基质中高度表达，并且也在原发性癌症相关成纤维细胞（CAF）中表达。敲除该酶导致CAF的许多特征逆转，并减弱其在体外和体内促进癌细胞生长的能力。在此期间，项目团队成功优化了一种生物化学试验，用于筛选10万多种化合物对NNMT的抑制活性。对测定的两个组分和三种相关甲基转移酶进行反筛选，以滤出假阳性。鉴定了具有有利活性特征的几种化学型，并评估了体外靶标接合和细胞抑制。已经获得了许多命中化合物与重组人NNMT的共晶体结构，并用于指导药物化学工作。在该项目被化学生物学联盟（CBC）管理下的NCI实验治疗（NExT）计划接受后，四种具有吸引人的药物样特性的强效和选择性三唑酮类似物已在单剂量小鼠药代动力学-药效学实验中进行了表征，两种化合物正在卵巢癌动物模型中进行概念验证有效性实验。正在进行的和未来的活动将集中在这些化合物和未来类似物与卵巢癌标准治疗相结合的多种疗效和生存模型的进一步表征。