2. Academic Validation
  3. Discovery of 4-(2-(methylamino)thiazol-5-yl)pyrimidin-2-amine derivatives as novel cyclin-dependent kinase 12 (CDK12) inhibitors for the treatment of esophageal squamous cell carcinoma

Discovery of 4-(2-(methylamino)thiazol-5-yl)pyrimidin-2-amine derivatives as novel cyclin-dependent kinase 12 (CDK12) inhibitors for the treatment of esophageal squamous cell carcinoma

  • Bioorg Chem. 2025 May:158:108302. doi: 10.1016/j.bioorg.2025.108302.
Yin Cao 1,  Sen Huang 1,  Yaohui He 2,  Yuxiang Zhang 1,  Simian Chen 1,  Mengxian Huang 3,  Fengming He 1,  Shutong Chen 1,  Di Wang 4,  Ziying Yang 1,  Xinwei Zhao 5,  Xiumin Wang 1,  Zhen Wu 1,  Mingtao Ao 6,  Yingkun Qiu 7,  Meijuan Fang 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
  • 2 State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China; MOE Key Lab of Rare Pediatric Diseases, Hengyang Medical School, University of South China, Hengyang 421001, China.
  • 3 State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China; Technical Innovation Center for Utilization of Marine Biological Resources, Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, China.
  • 4 State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China; School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Benxi 117004, China.
  • 5 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China.
  • 6 State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China; School of Pharmacy, Hubei University of Science and Technology, Xianning 437100, China. Electronic address: aomingtao@hbust.edu.cn.
  • 7 State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China. Electronic address: qyk@xmu.edu.cn.
  • 8 State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China. Electronic address: fangmj@xmu.edu.cn.
PMID: 40056603 DOI: 10.1016/j.bioorg.2025.108302
Abstract

The transcriptional cyclin-dependent protein kinase 12 (CDK12), a potential target in various cancers, was recently discovered with a dramatic amplification in esophageal Cancer (EC). In this study, we conducted an online database analysis that revealed CDK12 to be overexpressed in esophageal squamous cell carcinoma (ESCC) tissue samples from patients. Furthermore, survival analysis indicated that CDK12 can serve as a prognostic indicator for ESCC patients. In addition, CDK12 knockdown had been shown to reduce the proliferation of ESCC cells. The present study also details the design, synthesis, and biological evaluation of new CDK12 inhibitors which bear the scaffold of 4-(2-(methylamino)thiazol-5-yl)pyrimidin-2-amine. Among the synthesized compounds, H63 has been identified as a potent inhibitor of CDK12 with excellent anti-ESCC activity. Mechanistically, H63 blocked transcription elongation, downregulated the G1-phase core genes to induce cell cycle arrest, and altered the CDK12-ATM/ATR-CHEK1/CHEK2 signaling axis to cause DNA damage. In addition, H63 exhibited favorable pharmacokinetic properties, good safety, and prominent anti-ESCC activity in vivo. The present study suggests that CDK12 is a promising target for ESCC treatment, and H63 is a promising candidate for further clinical development as an anti-ESCC drug.

Keywords

4-(2-(methylamino)thiazol-5-yl)pyrimidin-2-amine; CDK12 inhibitor; DNA damage repair; ESCC.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-173147
    CDK12 Inhibitor
    CDK