热休克蛋白Hsp90 C-端调控剂的发现、设计及其化学生物学研究

热休克蛋白Hsp90与肿瘤的发生发展关系非常密切，针对它开展高效合理的药物分子设计研究具有非常重要的科研价值。本课题组前期研究发现类天然产物CPUY032018对Hsp90 C-端具有较好的结合活性和抑制活性。针对目前C-端调控剂结构单一，靶向性较差等问题，本项目以CPUY032018为探针分子，综合运用药物设计学，信息学和化学生物学等多种技术手段，优化并设计活性分子，深入挖掘Hsp90 C-端与调控剂的作用特征和结合模式，寻找Hsp90 C-端关键热区，以此建立高效准确的研究模型，开发结构新颖、活性明确的Hsp90 C-端调控剂。同时建立多方法联用、多层次交叉验证的生物活性评价体系，确保研究结果合理、可靠、高效。最终实现集发现、分子设计、合成以及生物活性评价于一体的Hsp90 C-端调控剂开发体系，为抗肿瘤药物研究提供候选化合物。

Hsp90 is considered to stand at the center of oncogenic proteostasis. Inhibition of Hsp90 is a very effective direction for anticancer drug development. Discovery of novel Hsp90 C-terminal modulator is also the main thesis of this project. In previous study we have found that CPUY032018 have a good inhibitory and affinity to Hsp90 C-terminal. Considering the current existing problems of C-terminal modulator, the project will clarify the binding interactions between Hsp90 C-terminal and modulators by using the medicinal chemistry and chemical biology methods with the probe of CPUY032018. We are committed to finding the hotspots of the Hsp90 C-terminal and then developing the novel structure and target-specific Hsp90 C-terminal modulator. Meanwhile we will establish a multi-level system to evaluate the biological activity of modulator. Under this system we will provide one or two candidate compound for anticancer drug research.