以Hsp90与Akt之间的结合为靶点的新型Akt抑制剂FM807及其抗肿瘤机制

项目名称： 以Hsp90与Akt之间的结合为靶点的新型Akt抑制剂FM807及其抗肿瘤机制

项目编号： No.81202561

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 叶敏

作者单位： 福建医科大学

项目金额： 23万元

中文摘要： Akt作为PI3K/Akt通路上的重要一员，是新型抗肿瘤药物分子作用靶点的研究热点。从以往的研究结果，我们提出Hsp90抑制剂可以促进Akt从Hsp90复合物解离，进而受蛋白磷酸酶PP2A的脱磷酸化调节，从而降低Akt活性的假说。以往有关Hsp90抑制剂通过PP2A调节p-Akt的研究至今未见文献报道，说明本课题具有一定的新颖性和独创性。在课题组长期进行Hsp90功能的研究基础上，本研究利用计算机模拟技术（三维定量构效关系、高通量虚拟筛选等），构建了以Hsp90和Akt的结合为靶点的药物筛选平台，研究筛选产物对Akt磷酸化和去磷酸化平衡的调节与Akt活性的关系，为开发新型的Akt抑制剂奠定理论基础，对解决目前Hsp90抑制剂缺少特异性的弊病有重要意义。在对本实验室内部的化合物库的筛选过程中，发现打分函数较高有代表性的筛选产物FM807，并且对此化合物进行初步的抗肿瘤机制研究。

中文关键词： HSP90；姜黄素衍生物；AKT；鼻咽癌；FM807

英文摘要： As an important member of PI3k/Akt pathway, Akt has always been a hot target in anti-tumor development. Previous research suggested that Hsp90 inhibitor could inhibit the interaction between Hsp90 and Akt, caused Akt lose the protection from Hsp90 then dephosphatase by PP2A. That is a new approach for developing the new type Akt inhibitor targeting both Hsp90 and Akt. Based on our fundamental research for Hsp90 function, we used computer simulation technology (Molecular docking and High-throughput screening) to construct an In silico screen model, providing the plat for screening the new small molecular compound which could cause the barrier between Hsp90 and Akt. This project will provide a new mechanism and method for developing the new type Akt inhibitor, also could be a solution for the present Hsp90 inhibitor which is lack of selectivity. During the screening process running in our lab compound libiliary, we found a prominent compund named FM807, which has high score and fit the pocket of Hsp90 very well. The initial research of anti-tumor mechanism about this canditate has been done.

英文关键词： HSP90；Curcumin analogue；AKT；Nasopharyngeal carcinoma；FM807