Lu Hongfu, Sun Deheng, Wang Zhen, Cui Hui, Min Lihua, Zhang Haoyu, Zhang Yihong, Wu Jianping, Cai Xin, Ding Xiao, Zhang Man, Aliper Alex, Ren Feng, Zhavoronkov Alex
Insilico Medicine Shanghai Ltd, Suite 901, Tower C, Changtai Plaza, 2889 Jinke Road, Pudong New District, Shanghai 201203, China.
Insilico Medicine AI Ltd, Masdar City, Abu Dhabi 145748, UAE.
J Med Chem. 2025 Feb 27;68(4):4148-4167. doi: 10.1021/acs.jmedchem.4c01616. Epub 2025 Feb 13.
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 as a novel, potent, orally available covalent CDK12/13 dual inhibitor with a promising safety profile and robust antitumor properties.
细胞周期蛋白依赖性激酶12和13（CDK12/13）通过在DNA损伤反应（DDR）中优先调节基因表达来维护基因组完整性。CDK12/13介导的DDR基因和通路的上调显著促进肿瘤发生和抗肿瘤治疗耐药性的发展。因此，对CDK12/13的功能抑制为对抗癌症发生提供了一种有吸引力的策略，特别是对于难治性和治疗耐药性癌症。在此，我们报告发现化合物 作为一种新型、强效、口服可用的共价CDK12/13双重抑制剂，具有良好的安全性和强大的抗肿瘤特性。
