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| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
Bioorganic chemistry
2025
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/40056603/ |
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Table of Contents:
- 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. Cao, Yin Huang, Sen He, Yaohui Zhang, Yuxiang Chen, Simian Huang, Mengxian He, Fengming Chen, Shutong Wang, Di Yang, Ziying Zhao, Xinwei Wang, Xiumin Wu, Zhen Ao, Mingtao Qiu, Yingkun Fang, Meijuan Humans Esophageal Squamous Cell Carcinoma Cyclin-Dependent Kinases Esophageal Neoplasms Antineoplastic Agents Protein Kinase Inhibitors Structure-Activity Relationship Cell Proliferation Molecular Structure Dose-Response Relationship, Drug Animals Drug Screening Assays, Antitumor Drug Discovery Mice Pyrimidines Mice, Nude Cell Line, Tumor 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.