Discovery of potent and selective CDK2 inhibitors with high safety and favorable bioavailability for the treatment of cancer

  • Eur J Med Chem. 2025 Jun 5:290:117503. doi: 10.1016/j.ejmech.2025.117503.
Weijiao Chen  1 ,  Xujie Zhuang  2 ,  Yuanyuan Chen  2 ,  Linhu Shen  2 ,  Huanaoyu Yang  2 ,  Minjie Wang  2 ,  Guoyong Pan  2 ,  Jinke Tan  2 ,  Xu Pan  2 ,  Sikai Feng  2 ,  Kai Yuan  3 ,  Xiao-Yu Zhang  4 ,  Peng Yang  5
Affiliations
  • 1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing, 211198, China.
  • 2. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
  • 3. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: [email protected].
  • 4. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: [email protected].
  • 5. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: [email protected].
PMID: 40107208 DOI: 10.1016/j.ejmech.2025.117503
Abstract

Targeting cyclin-dependent kinases (CDKs) to inhibit the cell proliferation is considered as a promising strategy for the treatment of Cancer, and the success of selective CDK4/6 inhibitors proves this concept. CDK2 plays an important role in the cell cycle and proliferation for the CCNE1-amplifed cancers and CDK4/6 inhibitors resistant breast cancers. Therefore, selective inhibition of CDK2 become research hotspots. In our work, we achieved a potent and selective CDK2 Inhibitor 46 through virtual screening and systematic structural modification. Compound 46 could arrest cell cycle, promote Apoptosis, and induce senescence-related phenotypes for CCNE1-amplifed ovarian Cancer OVCAR3 cell line, and also displayed potent antitumor activity against OVCAR3 xenografts. Furthermore, 46 hold promise in overcoming resistance to CDK4/6 inhibitor. More significantly, 46 exhibited great safety properties and favorable pharmacokinetic profiles in vivo. All these results demonstrated that 46 was a potential candidate of novel Anticancer drugs.

Keywords
CDK; Cell cycle; Ovarian cancer; Resistance; Selective CDK2 inhibitors.
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