新型mTOR信号通路抑制剂及其抗肿瘤活性和作用机制研究

项目名称： 新型mTOR信号通路抑制剂及其抗肿瘤活性和作用机制研究

项目编号： No.U1402227

项目类型： 联合基金项目

立项/批准年度： 2015

项目学科： 管理科学

项目作者： 李艳

作者单位： 中国科学院昆明植物研究所

项目金额： 221万元

中文摘要： mTOR信号通路的调控异常与多种肿瘤的发生发展密切相关，是已被确证的重要抗肿瘤药物作用靶点，最近的研究表明mTOR信号通路参与了肿瘤干细胞的调控。基于高内涵分析技术我们对mTOR信号通路抑制剂进行了的筛选，发现系列新颖呋喃咪唑盐能够有效抑制mTOR信号通路，其中代表化合物B591可抑制体内外肿瘤的生长，更重要的是该化合物显著抑制乳腺肿瘤干细胞的增殖，极具研究价值和开发潜力。本项目拟综合利用化学生物学和现代药理学技术手段，系统评价B591的抗肿瘤药效和成药性，为咪唑盐化合物抗肿瘤药物研究奠定基础；深入解析B591抑制mTOR信号通路的作用机制和分子靶点，分析呋喃咪唑盐化合物的构效关系；重点研究B591抑制肿瘤干细胞的体内外活性和作用机制，探讨mTOR信号通路对肿瘤干细胞干性维持和自我更新的调控作用和机制，为mTOR通路抑制剂在靶向肿瘤干细胞药物中的可能应用提供理论依据。

中文关键词： mTOR信号通路；抗肿瘤；肿瘤干细胞；作用机制

英文摘要： mTOR (the mammalian target of rapamycin ) signaling plays central role in the regulation of cell survival, growth, and proliferation. Dysregulation of the signaling pathway often occurs in a variety of human cancers. Therefore, mTOR signaling has become as an important target for successfull anticancer agents development. During the screening for mTOR signaling pathway inhibitors, we found that B591, novel benzofuran-imidazolium salt derived from natural products, shows potent inhibitory activity. B591 inhibits the growth of a variety of human cancer cells in vitro and in vivo, and specially, inhibits markedly the proliferation of breast cancer stem cells. In this project, with biochemistry and chemical biology techniques, the detailed roles and mechanisms of B591, and the structure-activity relationship of the imdazolium salts, will be carried out. Further we will perform comprehensive pharmacological investigation to address its antitumor activity targeting the mTOR signaling and cancer stem cells. Especially, we will explore the detailed roles of B591 in the inhibition of cancer stem cells and address the unrevealed regulating mechanisms of mTOR signaling in the self-renewl of cancer stem cells. As for the novelty in the structure of B591, our study could discover novel inhibitors of mTOR signaling pathway, reveal new mechanisms of the signaling and will supply valuable candidate antitumor agents with cancer stem cells inhibitory potent specially.

英文关键词： mTOR signaling pathway;antitumor;cancer stem cells;mechanism