2. Academic Validation
  3. Discovery of potent and selective CDK2 inhibitors with high safety and favorable bioavailability for the treatment of cancer

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

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: cpuyk1993@163.com.
  • 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: xyzhang0918@163.com.
  • 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: pengyang@cpu.edu.cn.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-173310
    CDK2 Inhibitor
    CDK