基于靶向CDK9选择性定量降解策略的小分子合成及其抗肾透明细胞癌的分子机制研究

肾透明细胞癌是肾癌中最常见的一种亚型，由于具有高侵袭性，其药物治疗面临很大的挑战。文献报道，CDK9与肾癌细胞的增殖密切相关，可能是肾癌中的一个潜在药物靶点。本课题组前期研究发现，利用近年新兴的PROTAC策略能选择性定量降解CDK9，从而抑制肾透明细胞癌，这是一种极具潜力的肾癌药物治疗新方法。但是，申请人前期基于选择性CDK9抑制剂iCDK9改造而来的PROTAC分子的抗癌活性还有待提高，其作用机制也需进一步明确。因此，针对CDK9靶点，本项目将结合现代计算机辅助药物设计以及有机合成技术，对iCDK9进行进一步的结构优化，以此开发活性更高的CDK9降解剂；期望通过系统的生物活性评价和构效关系分析，探讨这些CDK9降解剂选择性定量降解CDK9的分子结构基础，并研究其降解CDK9从而抑制肾透明细胞癌的分子机制，最终发现活性更强、成药性更好的靶向CDK9选择性定量降解的抗肾癌先导化合物。

Clear cell renal cell carcinoma (ccRCC) is one of the most common subtype of renal cell carcinoma (RCC) with high invasiveness, which provide great challenge for drug therapy. Recent studies have shown that CDK9 is closely related to the proliferation of renal clear cell carcinoma cells, which is proven to be a potential therapeutic target for ccRCC. In our previous work, we found that emerging PROTAC strategy could selectively and quantitatively degrade CDK9 to inhibit proliferation and invasion in ccRCC cell lines. Therefore, PROTAC is thought to be a promising therapeutic means for renal cancer. However, the anti-cancer activities of PROTACs previously synthesized, which are based on iCDK9, a selective CDK9 inhibitor, remain to be further improved. Herein, we will further optimize the structure of iCDK9 by combining the modern computer-aided drug design and organic synthesis technology, so as to develop novel PROTACs with better activities. Furthermore, biological activities and structure-activity relationship will be systematically discussed to explore the molecular structure basis of the selective and quantitative degradation of CDK9. Besides, optimal compounds will be applied as a probe molecule to investigate the molecular mechanism about how selective degradation of CDK9 exerts anti-proliferation activity in ccRCC. Ultimately, we aim to develop novel specific lead compounds with stronger activity and better druggability, which induce elective and quantitative degradation of CDK9 to treat renal cancer.