Design, Synthesis, and Biological Evaluation of Novel Orally Available Covalent CDK12/13 Dual Inhibitors for the Treatment of Tumors

  • J Med Chem. 2025 Feb 27;68(4):4148-4167. doi: 10.1021/acs.jmedchem.4c01616.
Hongfu Lu  1 ,  Deheng Sun  1 ,  Zhen Wang  1 ,  Hui Cui  1 ,  Lihua Min  1 ,  Haoyu Zhang  1 ,  Yihong Zhang  1 ,  Jianping Wu  1 ,  Xin Cai  1 ,  Xiao Ding  1 ,  Man Zhang  1 ,  Alex Aliper  2 ,  Feng Ren  1 ,  Alex Zhavoronkov  1  2  3
Affiliations
  • 1. Insilico Medicine Shanghai Ltd, Suite 901, Tower C, Changtai Plaza, 2889 Jinke Road, Pudong New District, Shanghai 201203, China.
  • 2. Insilico Medicine AI Ltd, Masdar City, Abu Dhabi 145748, UAE.
  • 3. Insilico Medicine Hong Kong Ltd, Hong Kong Science and Technology Park, Hong Kong 999077, China.
PMID: 39948720 DOI: 10.1021/acs.jmedchem.4c01616
Abstract

Cyclin-dependent Kinases 12 and 13 (CDK12/13) safeguard genomic integrity by preferentially regulating gene expression in the DNA damage response (DDR). The CDK12/13-mediated upregulation of DDR genes and pathways significantly contributes to both tumorigenesis and the development of resistance to antitumor therapies. Thus, the functional inhibition of CDK12/13 offers an attractive strategy to combat carcinogenesis, particularly for refractory and treatment-resistant cancers. Here, we report the discovery of compound 12b as a novel, potent, orally available covalent CDK12/13 dual inhibitor with a promising safety profile and robust in vivo antitumor properties.

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