用于治疗肿瘤的新型口服共价 CDK12/13 双抑制剂的设计、合成和生物学评估。

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-02-13 DOI:10.1021/acs.jmedchem.4c01616

Hongfu Lu, Deheng Sun, Zhen Wang, Hui Cui, Lihua Min, Haoyu Zhang, Yihong Zhang, Jianping Wu, Xin Cai, Xiao Ding, Man Zhang, Alex Aliper, Feng Ren, Alex Zhavoronkov

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本文章由计算机程序翻译，如有差异，请以英文原文为准。

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

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

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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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.