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

Jindi Huang; Ya He; Sumeng Chen; Ran Ren; Shipeng Zhang; Ji-Quan Zhang; Zhang Zhang; Tie-Gen Chen; Ling Wang

doi:10.1016/j.ejmech.2025.117367

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. Epub 2025 Feb 5.

Authors

Jindi Huang¹, Ya He¹, Sumeng Chen¹, Ran Ren², Shipeng Zhang¹, Ji-Quan Zhang³, Zhang Zhang⁴, Tie-Gen Chen⁵, Ling Wang⁶

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.

MeSH terms

Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Apoptosis* / drug effects
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation* / drug effects
Cyclin-Dependent Kinase 9* / antagonists & inhibitors
Cyclin-Dependent Kinase 9* / metabolism
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor*
Humans
Molecular Structure
Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors
Poly (ADP-Ribose) Polymerase-1 / metabolism
Poly(ADP-ribose) Polymerase Inhibitors* / chemical synthesis
Poly(ADP-ribose) Polymerase Inhibitors* / chemistry
Poly(ADP-ribose) Polymerase Inhibitors* / pharmacology
Protein Kinase Inhibitors* / chemical synthesis
Protein Kinase Inhibitors* / chemistry
Protein Kinase Inhibitors* / pharmacology
Structure-Activity Relationship

Substances

Cyclin-Dependent Kinase 9
Antineoplastic Agents
CDK9 protein, human
Protein Kinase Inhibitors
Poly(ADP-ribose) Polymerase Inhibitors
Poly (ADP-Ribose) Polymerase-1