Novel Inhibitors of Human N-Myristoyltransferase

人 N-肉豆蔻酰转移酶的新型抑制剂

• 批准号: 6783412
• 负责人: YAN ZHUANG
• 金额: $ 24.23万
• 依托单位: APOGEE BIOTECHNOLOGY CORPORATION
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6783412
• 关键词: acyltransferase; antineoplastics; apoptosis; chemical synthesis; combinatorial chemistry; cytotoxicity; drug design /synthesis /production; enzyme inhibitors; fatty acylation; high performance liquid chromatography; laboratory mouse; mass spectrometry; molecular dynamics; myristates; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; pharmacokinetics; recombinant proteins; terminal nick end labeling

The goal of this project is to identify and characterize novel inhibitors of human N-myristoyltransferase (NMT) that are effective as cancer therapeutic agents. Studies have shown that NMT catalyzes critical steps in the processing of several oncoproteins, and that genetic inhibition of this process ablates carcinogenesis. NMT attaches a myristoyl lipid to the N-terminus of specific target proteins. This irreversible lipidation enables protein conformational changes, membrane association, and further posttranslational processing, all of which confer activity to these target proteins. Furthermore, NMT is overexpressed in various human cancers. This finding, in conjunction with the necessary processing of oncogene products, identifies NMT as a potential therapeutic target against cancer. Despite this accumulating evidence, pharmacological inhibition of NMT as a means of cancer therapy remains unexplored. To address this problem, we have initiated a project to discover and characterize small molecule inhibitors of human NMT. By developing a novel screening assay and testing a library of synthetic compounds, we identified two chemotypes that inhibit NMT activity: cyclohexyl-octahydro-pyrrolo[1,2- a]pyrazine (COPP) and adamantine-containing compounds (ACC). Compounds sharing these chemotypes were isolated from the library and demonstrated in vitro and in vivo potency. To develop proof of principle evaluations of the potential utility of these chemotypes, the following Specific Aims will be addressed in this project: 1. Design and synthesize analogs of cyclohexyl-octahydro-pyrrolo[1,2-a]pyrazines and adamantine-containing compounds using QSAR and computational enzyme docking studies. 2. Evaluate these compounds using purified recombinant human NMT and cell-based assays. 3. Determine the in vivo toxicity, pharmacokinetics and antitumor activity of lead NMT inhibitors.

该项目的目的是识别和表征作为癌症治疗剂有效的人类N- myristoyltransferase（NMT）的新型抑制剂。研究表明，NMT在加工几种癌蛋白的加工中催化了关键步骤，并且对该过程的遗传抑制消除了致癌作用。 NMT将肉豆蔻酰脂质连接到特定靶蛋白的N末端。这种不可逆的脂质可实现蛋白质构象变化，膜关联和进一步的翻译后加工，所有这些都赋予了这些靶蛋白的活性。此外，NMT在各种人类中过表达 癌症。这一发现与癌基产品的必要加工结合使用，将NMT鉴定为针对癌症的潜在治疗靶标。 尽管有积累的证据，但对NMT作为癌症治疗的一种手段的药理抑制仍未得到探索。为了解决这个问题，我们启动了一个项目，以发现和表征人NMT的小分子抑制剂。通过开发新的筛选测定并测试合成化合物的库，我们确定了两种抑制NMT活性的化学型：环己基 - 辛格氏甲状腺 - 吡咯洛洛[1,2- A]吡嗪（COPP）（COPP）（COPP）和含有阿甘坦汀的化合物（ACC）。从文库中分离出共享这些化学型的化合物，并在体外和体内表现出来。为了制定原理评估这些化学型的潜在效用的证明，将在此解决以下具体目标 项目： 1。使用QSAR和计算酶对接研究研究的环己基 - 辛格德罗 - 吡咯并合成类似物的类似物和含有金刚烷的化合物的类似物。 2。使用纯化的重组人NMT和基于细胞的测定法评估这些化合物。 3。确定铅NMT抑制剂的体内毒性，药代动力学和抗肿瘤活性。