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

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

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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