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.

该项目的目标是鉴定和表征可有效作为癌症治疗剂的新型人类 N-肉豆蔻酰转移酶 (NMT) 抑制剂。研究表明，NMT 催化多种癌蛋白加工过程中的关键步骤，而对该过程的基因抑制可消除致癌作用。 NMT 将肉豆蔻酰脂质附着到特定目标蛋白的 N 末端。这种不可逆的脂化使蛋白质构象发生变化、膜缔合以及进一步的翻译后加工，所有这些都赋予这些靶蛋白活性。此外，NMT 在多种人类中过度表达。 癌症。这一发现与癌基因产物的必要加工相结合，将 NMT 确定为抗癌的潜在治疗靶点。 尽管证据不断积累，但 NMT 的药理抑制作为癌症治疗手段仍有待探索。为了解决这个问题，我们启动了一个项目来发现和表征人类 NMT 的小分子抑制剂。通过开发一种新的筛选方法并测试合成化合物库，我们确定了两种抑制 NMT 活性的化学型：环己基-八氢-吡咯并[1,2-a]吡嗪 (COPP) 和含金刚烷的化合物 (ACC)。从文库中分离出具有这些化学型的化合物，并在体外和体内展示了效力。为了对这些化学型的潜在效用进行原则评估证明，本文将解决以下具体目标 项目： 1. 使用 QSAR 和计算酶对接研究设计和合成环己基-八氢-吡咯并[1,2-a]吡嗪和含金刚烷化合物的类似物。 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. 确定先导NMT抑制剂的体内毒性、药代动力学和抗肿瘤活性。