2. Academic Validation
  3. Design and synthesis of CDK9/EZH2 dual-target inhibitors to achieve synergistic antitumor effects

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

  • Eur J Med Chem. 2025 Sep 15:294:117773. doi: 10.1016/j.ejmech.2025.117773.
Lina Tian 1,  Jian Xiao 2,  Yanping Zeng 3,  Yangsha Li 2,  Aihuan Wei 4,  Qianqian Shen 5,  Yixue Han 6,  Yi Chen 7,  Youhong Hu 8
Affiliations

Affiliations

  • 1 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China.
  • 2 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 110039, China.
  • 3 School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, 1 Xiangshanzhi Road, Hangzhou, 310024, China.
  • 4 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China; State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
  • 5 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 6 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China.
  • 7 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 110039, China. Electronic address: ychen@simm.ac.cn.
  • 8 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 110039, China; School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, 1 Xiangshanzhi Road, Hangzhou, 310024, China; State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China. Electronic address: yhhu@simm.ac.cn.
PMID: 40403644 DOI: 10.1016/j.ejmech.2025.117773
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.

Keywords

CDK9; DLBCL; Dual target inhibitor; EZH2.

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