项目名称: 基于mTOR和Mnk1双靶点策略的苦参等5种中药抑制翻译起始活性成分研究
项目编号: No.81503211
项目类型: 青年科学基金项目
立项/批准年度: 2016
项目学科: 医药、卫生
项目作者: 张超
作者单位: 中国药科大学
项目金额: 18万元
中文摘要: 肿瘤细胞与正常细胞相比,翻译起始水平全局性上调,特别是一些细胞增殖、抗凋亡、血管生成、侵袭等相关蛋白的翻译起始效率上调得尤为显著。eIF4E是蛋白质翻译起始关键限速酶,eIF4E相关通路抑制剂也成为翻译起始抑制剂中的研究热点。但是,现有的eIF4E相关通路抑制剂主要是针对单一靶点(如mTOR、Mnk1),效果较差并极易诱导耐药。而针对不同靶点的eIF4E相关通路抑制剂联合使用可以起到协同增效作用。基于这一发现,本项目拟从双靶点角度建立新的eIF4E相关通路抑制剂筛选系统,并利用中药小分子化合物库,筛选出具有mTOR和Mnk1双重抑制活性的小分子化合物;并通过检测目标化合物对骨肉瘤细胞体内外增殖转移以及对于eIF4E介导翻译起始的作用,明确其抗肿瘤药效及机制。本项目开展将为从中药中挖掘靶向性抗肿瘤药物打下扎实的工作基础,也是为中药资源的合理开发提供重要依据。
中文关键词: 中药;翻译起始;真核起始因子4E;双靶点;抗肿瘤
英文摘要: Compared with normal cells, tumor cells exhibit high levels of global translation initiation, especially prefer to translate cell proliferation, anti-apoptosis, angiogenesis and invasion related proteins. eIF4E is the key enzyme controlling protein translation initiation. eIF4E-related pathway inhibitor has become a research hotspot in the investigation of translation initiation inhibitor.However, single target inhibitor (such as mTOR, Mnk1) has poor efficacy and is highly vulnerable to induce resistance. Interestingly, the combination of eIF4E-related pathway inhibitors targeting different kinase plays a synergistic effect. Based on this finding, the aim of this project is to establish a double-target screening system of eIF4E-related pathway inhibitors. We want to select small molecule compounds containing mTOR and Mnk1 dual inhibitory activity from the TEM small molecule library and detect its anti-osteosarcoma effect and the influence on eIF4E-mediated translation initiation.This work will make contribution to explore targeted antitumor drugs from TCM and provide scientific basis for the advancement and future development of TCM.
英文关键词: Traditional Chinese Medcine;Translation Initiation;eIF4E;Double-target;Antitumor