Academy of Medical Engineering and Translational Medicine (AMT), Tianjin University, Tianjin 300072, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China.
Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China.
Bioorg Chem. 2024 Jul;148:107456. doi: 10.1016/j.bioorg.2024.107456. Epub 2024 May 14.
The targeting of cyclin-dependent kinase 7 (CDK7) has become a highly desirable therapeutic approach in the field of oncology due to its dual role in regulating essential biological processes, encompassing cell cycle progression and transcriptional control. We have previously identified a highly selective thieno[3,2-d]pyrimidine-based CDK7 inhibitor with demonstrated efficacy and safety in animal model. In this study, we sought to optimize the thieno[3,2-d]pyrimidine core to discover a novel series of CDK7 inhibitors with improved potency and pharmacokinetic (PK) properties. Through extensive structure-activity relationship (SAR) studies, compound 20 has emerged as the lead candidate due to its potent inhibitory activity against CDK7 and remarkable efficacy on MDA-MB-453 cells, a representative triple negative breast cancer (TNBC) cell line. Furthermore, 20 has demonstrated favorable oral bioavailability and exhibited highly desirable pharmacokinetic (PK) properties, making it a promising lead candidate for further structural optimization.
靶向细胞周期蛋白依赖性激酶 7（CDK7）已成为肿瘤学领域极具吸引力的治疗方法，因为它在调节细胞周期进程和转录控制等基本生物学过程中具有双重作用。我们之前已经确定了一种高度选择性的噻吩并[3,2-d]嘧啶基 CDK7 抑制剂，在动物模型中具有疗效和安全性。在这项研究中，我们试图优化噻吩并[3,2-d]嘧啶核心，以发现一系列新型的 CDK7 抑制剂，提高其效力和药代动力学（PK）特性。通过广泛的构效关系（SAR）研究，由于其对 CDK7 的强大抑制活性和对 MDA-MB-453 细胞（代表性的三阴性乳腺癌（TNBC）细胞系）的显著疗效，化合物 20 脱颖而出，成为领先的候选药物。此外，20 具有良好的口服生物利用度，并表现出理想的药代动力学（PK）特性，使其成为进一步结构优化的有前途的候选药物。
