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

  • Bioorg Chem. 2024 Jul:148:107456. 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  8 ,  Dawei Ma  9 ,  Mengyang Fan  10
Affiliations
  • 1. 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.
  • 2. Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China.
  • 3. 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.
  • 4. 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.
  • 5. 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.
  • 6. Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 20032, China.
  • 7. 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.
  • 8. Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 20032, China. Electronic address: [email protected].
  • 9. Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 20032, China. Electronic address: [email protected].
  • 10. Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China. Electronic address: [email protected].
PMID: 38761706 DOI: 10.1016/j.bioorg.2024.107456
Abstract

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.

Keywords
Cyclin-dependent kinase 7; Small molecular inhibitor; Thieno[3,2-d]pyrimidine derivative; Triple negative breast cancer.
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