靶向Hsp90-Cdc37-Kinases体系的Cdc37抑制剂合理设计及其抗肿瘤作用机制研究

Hsp90-Cdc37-Kinases体系在蛋白激酶的成熟过程中至关重要，通过抑制Cdc37而特异性调控Hsp90-Cdc37-Kinases体系间复杂蛋白-蛋白相互作用有望成为靶向分子伴侣系统的抗肿瘤药物研发的新思路。本项目围绕Cdc37抑制剂研究中的关键科学问题开展如下工作：（1）研究苗头分子与Cdc37的结合腔穴的空间特征，分区域合理设计抑制剂衍生物，获得强效的Cdc37抑制剂并高效调控Hsp90-Cdc37-Kinases体系。（2）探索抑制Cdc37并干扰Hsp90-Cdc37-Kinases体系而实现抗肿瘤作用的生物机制。通过发现结构新颖、活性优异的Cdc37小分子抑制剂，选择性阻断蛋白激酶的成熟过程，为以Cdc37为靶点的抗肿瘤药物研发提供可靠的先导化合物及明晰的分子作用机制。

Hsp90-Cdc37-Kinases chaperone cycle plays a key role in the maturation process of protein kinases. Targeting Hsp90-Cdc37-Kinases chaperone cycle by a Cdc37 inhibition mechanism might be a promising strategy for the development of anti-tumor drugs through molecular chaperone system. This project will be performed based on the key scientific issues of the discovery of Cdc37 inhibitors: (1) To obtain potent Cdc37 inhibitors for Hsp90-Cdc37-Kinases inhibition, the binding site and the interaction mode will be studied based on structure-based drug design and characteristic of the target. (2) Exploration of the biological mechanism of the anti-cancer effect by inhibiting Cdc37 to interfere the Hsp90-Cdc37-Kinases chaperone cycle. Through the discovery of potent Cdc37 inhibitors and selectively blocking the maturation process of protein kinases, a reliable lead compound and a clear molecular mechanism will be identified for the development of anti-cancer drugs by targeting Cdc37.