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  3. Design, synthesis and biological evaluation of dual CDK9/PARP inhibitors for the treatment of cancer

Design, synthesis and biological evaluation of dual CDK9/PARP inhibitors for the treatment of cancer

  • Eur J Med Chem. 2025 Apr 5:287:117367. doi: 10.1016/j.ejmech.2025.117367.
Jindi Huang 1,  Ya He 1,  Sumeng Chen 1,  Ran Ren 2,  Shipeng Zhang 1,  Ji-Quan Zhang 3,  Zhang Zhang 4,  Tie-Gen Chen 5,  Ling Wang 6
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, Joint International Research Laboratory of Synthetic Biology and Medicine, Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, China.
  • 2 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, 510632, China.
  • 3 College of Pharmacy, Guizhou Medical University, Guiyang, 550004, China.
  • 4 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, 510632, China. Electronic address: zzmoxue@163.com.
  • 5 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China. Electronic address: chentiegen@simm.ac.cn.
  • 6 Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, Joint International Research Laboratory of Synthetic Biology and Medicine, Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, China. Electronic address: lingwang@scut.edu.cn.
PMID: 39947055 DOI: 10.1016/j.ejmech.2025.117367
Abstract

Combination of CDK9 and PARP inhibitors has demonstrated synergistic Anticancer activity in ovarian Cancer and triple-negative breast Cancer (TNBC). In this study, we report the design and discovery of a series of dual CDK9/PARP inhibitors by incorporating pharmacophores targeting CDK9 and PARP. Notably, compounds 31, 34, and 36 exhibited potent and well-balanced inhibitory activity against CDK9 and PARP1, with IC50 values in the nanomolar range. Additionally, these compounds exhibited broad-spectrum antiproliferative effects across multiple Cancer cell lines. Specifically, treatment with 36 in MDA-MB-231 cells induced Apoptosis, arrested the cell cycle at the G2/M phase and S phase, and inhibited cell migration by targeting both the CDK9 and PARP pathways. Treatment with 34 in MV4-11 cells can significantly inhibited CDK9 expression, its downstream signaling pathways, and PARP protein levels. The results of kinase profiling showed that 34 demonstrated excellent selectivity for CDK9 and PARP over Other CDK family members and kinases. Furthermore, 36 displayed excellent metabolic stability. These findings highlight the therapeutic potential of 34 and 36 as dual CDK9/PARP inhibitors, warranting further investigation and optimization.

Keywords

CDK9; Cancer; Dual inhibitor; PARP; Pharmacophore-fusion.

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