CDK9是肿瘤发生发展过程中关键分子之一，而目前在研的CDK9抑制剂普遍临床抗肿瘤效果不佳。本项目前期利用蛋白降解靶向嵌合体策略构建新型CDK9小分子调控剂，以期能够克服传统激酶抑制剂的缺陷，在体内/外获得良好抗肿瘤活性。蛋白降解靶向嵌合体（PROTACs）作为异型双官能团分子，类药性问题是该类化合物向药物转变的主要瓶颈。本项目创新性引入“生物正交化学”技术，通过构建基于细胞自组装的蛋白水解靶向嵌合体，以改善化合物理化性质等成药性指标。在分析CDK9蛋白与E3连接酶催化口袋特征的基础上，本项目首先拟从结构因素优化获得靶向CDK9及募集E3连接酶的配体分子，并引入特定标签官能团构建PROTACs分子，随后进行靶标亲合力及蛋白降解活性评价，探索最优功能取代基的配置方案。本项目兼顾抗肿瘤活性及类药性进行设计与结构优化，以发现高效、低毒的靶向CDK9的PROTACs分子作为新型抗肿瘤候选化合物。

CDK9 (cyclin dependent kinase 9) is one of the most critical molecules during tumor development. The currently investigated inhibitors of CDK9 showed poor antitumor activity in in vivo studies. Our research group has recently discovered a novel series of small-molecule modulators, which designed based on the strategy of proteolysis targeting chimeras (PROTACs), may avoid the defects of the traditional kinase inhibitors through degrading the expression level of CDK9. The small molecule PROTACs were expected to show good antitumor activity both in in vitro and in vivo. PROTACs are hetero-bifunctional with high molecular weight which can limit cellular permeation, solubility, and other drug-like properties. In this research, we introduce the bio-orthogonal chemistry technology to construct the in-cell click-formed proteolysis targeting chimeras (CLIPTACs), which may improve the drug-like properties of PROTACs. By analyzing the catalytic pocket of CDK9 and E3 ubiquitin ligases, we are promoted to optimize the CDK9 targeting PROTACs based on the structural factors. Subsequently, the specific tagged group were introduced to the ligands to form CLIPTACs. Further through evaluating the target affinity and protein degradation activity, the optimal functional substituents of PROTACs were ought to be obtained. With fully consideration of the biological activity and druggability during the design and optimization of small molecule PROTACs, we prospect to discover compounds targeting CDK9 as novel antitumor candidates with high potency and low toxicity.