基于结构的新型CDK7抑制剂的设计、合成及其抗肿瘤活性

根据细胞周期依赖性激酶7(CDK7)的蛋白结构, 利用Discovery Studio 2.1程序包中的LigandFit模块建立了CDK7抑制剂的分子对接模型, 采用受试者工作特征曲线(ROC)方法选择LigScore2为最佳打分函数(ROC曲线下的面积为0.95), 并验证了该模型的准确性. 利用该模型对设计的化合物与CDK7蛋白进行对接分析, 得到了2个打分最高的化合物16、17, 进而通过13步的合成路线, 以中等至高的收率得到目标化合物, 并测定其体外抗肿瘤活性. 结果表明, 所合成的化合物对急性前髓细胞性白血病细胞(HL60)、鼻咽癌细胞(KB)、肝肿瘤细胞(SMMC-7721)、结肠腺癌细胞(HCT-116)、肺癌细胞(A549)细胞株均有抑制作用(IC50值为0.84-19.70 μmol·L-1), 其中化合物16对HL60细胞株的IC50值最低, 为0.84 μmol·L-1.

Structure-Based Drug Design, Synthesis and Antitumor Activities of Novel CDK7 Inhibitors

A novel and reliable docking model based on the protein structure of cyclin dependent kinase 7 (CDK7) for CDK7 inhibitors was developed using LigandFit module within Discovery Studio 2.1 package. Receiver operating characteristic curves (ROC) were applied as a method of validation to evaluate the accuracy of the established model. LigScore2 was selected as the best score function. The area under curve (AUC) of the ROC curve was 0.95. Compounds designed by our group were docked with CDK7 to study the binding mode between the target molecules and the receptor protein CDK7. Two compounds, namely 16 and 17, with favorable scores from the docking studies were selected for synthesis and required a thirteen-step route but they were obtained in moderate to good yields. The two synthesized compounds were then evaluated for their in vitro cytotoxic activities against five human cancer cell lines including human acute promyelocytic leukemia cells (HL60), human nasopharynx carcinoma cells (KB), human hepatoma cells (SMMC-7721), human colon adenocarcinoma cells (HCT-116), and human lung cancer cells (A549). Both tested compounds showed potent cytotoxic activities with IC50 values ranging from 0.84 to 19.70 μmol·L-1 . Compound 16 showed the most potent antitumor activity against HL60 human cancer cell lines with IC50 value of 0.84 μmol·L-1.