2. Academic Validation
  3. Discovery and optimization of thieno[3,2-d]pyrimidine derivatives as highly selective inhibitors of cyclin-dependent kinase 7

Discovery and optimization of thieno[3,2-d]pyrimidine derivatives as highly selective inhibitors of cyclin-dependent kinase 7

  • Eur J Med Chem. 2024 Jan 5:263:115955. doi: 10.1016/j.ejmech.2023.115955.
Hongjin Zhang 1,  Guohao Lin 2,  Suyun Jia 3,  Ying Zhang 4,  Jianbo Wu 4,  Yanxin Tao 5,  Weixue Huang 6,  Meiru Song 2,  Ke Ding 7,  Dawei Ma 8,  Mengyang Fan 9
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 Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 20032, China. Electronic address: [email protected].
  • 8 Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 20032, China. Electronic address: [email protected].
  • 9 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: 38000213 DOI: 10.1016/j.ejmech.2023.115955
Abstract

Targeting cyclin-dependent kinase 7 (CDK7) has emerged as a highly sought-after therapeutic strategy in oncology due to its duality of function in regulating biological processes, including cell cycle progression and transcriptional control. Herein, we describe the design, optimization and characterization of a series of thieno[3,2-d]pyrimidine derivatives as potent CDK7 inhibitors. The involvement of thiophene as core structure plays critical role in leading to the remarkable selectivity and incorporation of a fluorine atom into the piperidine ring enhances metabolic stability. Structure-activity relationship (SAR) study generated compound 36 as lead compound with potent inhibitory activity against CDK7 and good kinome selectivity in vitro. Compound 36 demonstrated strong efficacy against a triple negative breast Cancer (TNBC) cell line-derived xenograft (CDX) mouse model upon oral administration at 5 mg/kg once daily. Therefore, it exhibits immense potential as a lead candidate for further exploration in the development of Cancer therapy.

Keywords

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

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