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

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

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: dingk@sioc.ac.cn.
  • 9 Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 20032, China. Electronic address: madw@sioc.ac.cn.
  • 10 Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China. Electronic address: sioc.mengyangfan@gmail.com.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-163721
    CDK7 Inhibitor
    CDK