靶向Hsp90α和Aha1的双靶点抗肿瘤抑制剂发现及其作用机制研究

分子伴侣蛋白Hsp90是抗肿瘤药物研发的热门靶点，目前已有18个Hsp90 ATP结合抑制剂进入临床研究阶段，但未达理想的药效和诱发的热休克反应阻碍了它们上市的步伐。除了受ATP/ADP调控外，Hsp90的功能执行还同时被多种共伴侣蛋白精密调节。其中，Aha1是已知的唯一一个显著增强Hsp90 ATP酶活性的共伴侣蛋白，同时它也是一个与Hsp90有协同作用的潜在抗肿瘤药物研发靶点，开发靶向Hsp90-Aha1互作体系的抑制剂有望在抑制肿瘤的同时规避热休克反应的产生。本项目拟开发同时靶向Hsp90α和Aha1的双靶点抗肿瘤抑制剂，并在分子和细胞水平阐明抑制剂的效应机制。项目成果将为解析Hsp90α-Aha1互作体系的功能执行相关动态结构特征提供新的数据支持；为明确Hsp90α-Aha1互作体系作为抗肿瘤药物研发靶标的可行性提供参考数据；为开发靶向Hsp90的抗肿瘤候选药物提供新型源头化合物。

Molecular chaperone Hsp90 is an established target for anti-cancer drug development. Up to date, a total number of 18 ATP-competitive inhibitors targeting the ATP-binding pocket of Hsp90 have progressed into the different phases of clinical trials. However, none of them has been approved for cancer therapy, and this could be at least partially attributed to the limited clinical efficacy and the induced heat shock response associated with the application of Hsp90 ATP-competitive inhibitors. Besides ATP and ADP molecules, tens of co-chaperone proteins are also involved in regulating the functional display of Hsp90. Among the identified co-chaperones of Hsp90, Aha1 is the only co-chaperone known to strongly accelerate the ATPase cycle of Hsp90. It works synergistically with Hsp90, and serves as a potential target for anti-cancer drug development. The protein-protein interaction inhibitors, which targeting the Hsp90-Aha1 functioning system, might potentially inhibit the development of cancer without triggering heat shock response. Here in this project, we will develop dual inhibitors of Hsp90α and Aha1, and then elucidate the working mechanisms of these compounds at both the molecular level and the cellular level. The findings through conducting this project will provide new data for elucidating the dynamic structural features of the Hsp90α-Aha1 functioning system by using the inhibitors as probes, and also key information for assessing the druggability of the Hsp90α-Aha1 interacting system. Besides, Hsp90-targeted novel anti-cancer drug leads will be obtained.