Design, synthesis and evaluation of thieno[3,2-d]pyrimidine derivatives as novel potent CDK7 inhibitors,Bioorganic Chemistry

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Design, synthesis and evaluation of thieno[3,2-d]pyrimidine derivatives as novel potent CDK7 inhibitors
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2024-05-14 , DOI: 10.1016/j.bioorg.2024.107456
Hongjin Zhang ₁ , Guohao Lin ₂ , Suyun Jia ₃ , Jianbo Wu ₄ , Ying Zhang ₄ , Yanxin Tao ₅ , Weixue Huang ₆ , Meiru Song ₇ , Ke Ding ₆ , Dawei Ma ₆ , Mengyang Fan ₂

Affiliation

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.
Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; School of Molecular Medicine, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310024, China; Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 20032, China.
Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China.
Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; School of Molecular Medicine, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310024, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of of Life Sciences, Tianjin University, Tianjin 300072, China.
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 20032, China.
Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China; Institute of Chemistry, Henan Academy of Sciences, Zhengzhou, Henan 450046, China.

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-]pyrimidine-based CDK7 inhibitor with demonstrated efficacy and safety in animal model. In this study, we sought to optimize the thieno[3,2-]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 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, has demonstrated favorable oral bioavailability and exhibited highly desirable pharmacokinetic (PK) properties, making it a promising lead candidate for further structural optimization.

中文翻译：

作为新型有效 CDK7 抑制剂的噻吩并[3,2-d]嘧啶衍生物的设计、合成和评估

细胞周期蛋白依赖性激酶 7 (CDK7) 的靶向治疗已成为肿瘤学领域非常理想的治疗方法，因为它在调节基本生物过程（包括细胞周期进程和转录控制）方面发挥着双重作用。我们之前已经鉴定出一种高度选择性的基于噻吩并[3,2-]嘧啶的CDK7抑制剂，并在动物模型中证明了其有效性和安全性。在这项研究中，我们试图优化噻吩并[3,2-]嘧啶核心，以发现一系列具有改进效力和药代动力学 (PK) 特性的新型 CDK7 抑制剂。通过广泛的构效关系（SAR）研究，该化合物因其对 CDK7 的有效抑制活性以及对代表性三阴性乳腺癌（TNBC）细胞系 MDA-MB-453 细胞的显着疗效而成为主要候选药物。此外，已表现出良好的口服生物利用度，并表现出非常理想的药代动力学 (PK) 特性，使其成为进一步结构优化的有前途的主要候选药物。

更新日期：2024-05-14

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