靶向Hsp90中间结构域的新型抗肿瘤抑制剂发现及其效应机制研究

分子伴侣Hsp90是抗肿瘤药物研发的靶点，现已有17个靶向Hsp90 N端ATP结合口袋的抑制剂进入临床实验阶段。然而，尚未有相关药物获批上市，毒副作用是导致这种结果的重要原因。由于这些ATP结合抑制剂同样会对Hsp90同家族（GHL-ATPases）的其他成员产生作用，从而在抑制肿瘤的同时产生较大的毒副作用。开发靶向Hsp90中间结构域的变构和/或蛋白-蛋白相互作用抑制剂有望实现在抑制肿瘤的同时减少毒副作用的产生。然而，目前尚无中间结构域非共价抑制剂被发现。在本项目工作中，我们拟通过实验筛选和基于结构的药物化学改造获得靶向Hsp90中间结构域的新型抗肿瘤抑制剂，并在解析抑制剂作用机制的同时兼顾探索Hsp90中间结构域的结构和功能特征。项目的研究成果将为明确Hsp90中间结构域是否可以做为抗肿瘤药物研发的靶点提供信息，并为开发毒副作用小的靶向Hsp90的抗肿瘤候选药物提供新型的先导化合物。

Molecular chaperone Hsp90 is an established target for anti-cancer drug development. Up to date, a total number of 17 ATP-competitive inhibitors targeting the ATP-binding pocket of Hsp90 have progressed into the different phases of clinical trial. However, none of them has been officially approved for cancer therapy, and the significant side effects of these inhibitors are one of the major causes. Hsp90 belongs to the GHL-ATPase subfamily, and the ATP-competitive inhibitors of Hsp90 will definitely affect the function display of the other GHL-ATPase subfamily members. We then hypothesize that the allosteric and/or protein-protein interaction inhibitors, which targeting the middle domain of Hsp90, might potentially inhibit the development of cancer with lesser side effects. Due to the distinct structure and function features of the middle domain of Hsp90, no non-covalent inhibitor targeting this domain has been reported yet. Therefore, here in this project, we will develop Hsp90 middle domain-targeted anti-cancer inhibitors by a combination use of experimental screening and structure-based medicinal chemistry optimization. And in the following studies we will elucidate the working mechanisms of these inhibitors and explore the structural features of the Hsp90 middle domain associated with its different functional states by using the inhibitors as probes. The findings through conducting this project will provide important information for assessing the druggability of the Hsp90 middle domain, and also the novel type of anti-cancer drug leads with lesser side effects.