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

文献类型：期刊论文

作者Tian, Lina6; Xiao, Jian4,5; Zeng, Yanping3; Li, Yangsha4,5; Wei, Aihuan2,6; Shen, Qianqian5; Han, Yixue1,6; Chen, Yi4,5,6; Hu, Youhong1,2,3,4,6
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-09-15
卷号294页码:14
关键词CDK9 EZH2 Dual target inhibitor DLBCL
ISSN号0223-5234
DOI10.1016/j.ejmech.2025.117773
英文摘要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.
WOS关键词DEPENDENT KINASE 9 ; CDK9 INHIBITION ; CANCER ; DISCOVERY ; POTENT ; MOLECULE ; MCL-1 ; EZH2
资助项目Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM0320231003] ; Shandong Laboratory Program[SYS202205] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB1060401]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001498479100002
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/318168]  
专题新药研究国家重点实验室
通讯作者Chen, Yi; Hu, Youhong
作者单位1.Anhui Univ Chinese Med, Sch Pharm, Hefei 230012, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, 555 ZuChongZhi Rd, Shanghai 201203, Peoples R China
3.Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, 1 Xiangshanzhi Rd, Hangzhou 310024, Peoples R China
4.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 110039, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
6.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
推荐引用方式
GB/T 7714		 Tian, Lina,Xiao, Jian,Zeng, Yanping,et al. Design and synthesis of CDK9/EZH2 dual-target inhibitors to achieve synergistic antitumor effects[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2025,294:14.
APA Tian, Lina.,Xiao, Jian.,Zeng, Yanping.,Li, Yangsha.,Wei, Aihuan.,...&Hu, Youhong.(2025).Design and synthesis of CDK9/EZH2 dual-target inhibitors to achieve synergistic antitumor effects.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,294,14.
MLA Tian, Lina,et al."Design and synthesis of CDK9/EZH2 dual-target inhibitors to achieve synergistic antitumor effects".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 294(2025):14.

入库方式： OAI收割

来源：上海药物研究所

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