Design and synthesis of CDK9/EZH2 dual-target inhibitors to achieve synergistic antitumor effects

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-05-17 DOI:10.1016/j.ejmech.2025.117773

Lina Tian , Jian Xiao , Yanping Zeng , Yangsha Li , Aihuan Wei , Qianqian Shen , Yixue Han , Yi Chen , Youhong Hu

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Abstract

Cyclin-dependent kinase 9 (CDK9) plays a pivotal role in regulating transcriptional elongation and has emerged as a promising target in cancer therapy. However, it is reported that CDK9 inhibitors cause abnormal upregulation of H3K27me3 in Diffuse Large B-cell Lymphoma (DLBCL) cell lines. Here, we designed a series of dual inhibitors targeting CDK9 and EZH2 by linking two distinct pharmacophores to achieve synergistic antitumor effects. Among these, the potent CDK9/EZH2 inhibitor D16 exhibited impressive inhibitory activities, with IC₅₀ values of 83.9 nM for CDK9 and 108.6 nM for EZH2. Notably, compound D16 induced more significant DNA damage and exhibited greater inhibition of DLBCL proliferation than the single-target inhibitor SNS-032 or C24. In addition, D16 showed potent anti-proliferative activities in various solid tumor cell lines, which may provide an innovative strategy for the treatment of cancer.

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设计合成CDK9/EZH2双靶点抑制剂，实现协同抗肿瘤作用

细胞周期蛋白依赖性激酶9 （CDK9）在调节转录延伸中起着关键作用，并已成为癌症治疗中有希望的靶点。然而，有报道称CDK9抑制剂可引起弥漫性大b细胞淋巴瘤（DLBCL）细胞系中H3K27me3的异常上调。在这里，我们设计了一系列针对CDK9和EZH2的双抑制剂，通过连接两种不同的药效团来实现协同抗肿瘤作用。其中，有效的CDK9/EZH2抑制剂D16表现出令人印象深刻的抑制活性，对CDK9和EZH2的IC50值分别为83.9 nM和108.6 nM。值得注意的是，与单靶点抑制剂SNS-032或C24相比，化合物D16诱导的DNA损伤更显著，对DLBCL增殖的抑制作用更大。此外，D16在多种实体肿瘤细胞系中显示出强大的抗增殖活性，这可能为癌症的治疗提供一种创新策略。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.