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Updated: Jun 29, 2025

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

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Discovery of novel macrocyclic derivatives as potent and selective cyclin-dependent kinase 2 inhibitors

Pengpeng Niu1, Yanxin Tao2, Qingyuan Meng3

  • 1Academy of Medical Engineering and Translational Medicine (AMT), Tianjin University, Tianjin 300072, China; Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China.

Bioorganic & Medicinal Chemistry
|April 7, 2024
PubMed

Insights

Researchers optimized a novel macrocyclic inhibitor to target cyclin-dependent kinase 2 (CDK2), a key driver in various cancers. The optimized compound 22 shows potent CDK2 inhibition and selectivity, offering promise for new cancer drug development.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Cyclin-dependent kinase 2 (CDK2) regulates the cell cycle; its dysregulation drives cancer, particularly ovarian, uterine, and gastric cancers.
  • Developing selective CDK2 inhibitors is challenging due to conserved ATP-binding pockets across CDK family members.
  • Amplification of the CCNE1 gene is frequently associated with CDK2-driven cancers.

Purpose of the Study:

  • To optimize a novel macrocyclic inhibitor for enhanced selectivity and metabolic stability as a CDK2 inhibitor.
  • To identify a potent and selective lead compound for CDK2-targeted cancer therapy.

Main Methods:

  • Optimization of a lead macrocyclic inhibitor (compound 1) targeting CDK2/5/7/9.
  • Utilized molecular dynamic (MD) simulations to understand selectivity improvements against CDK5.
  • Characterized the inhibitory activity, selectivity, and cellular effects of optimized compounds.

Main Results:

  • Compound 22 demonstrated excellent CDK2 inhibitory activity.
  • Compound 22 exhibited significant selectivity over other CDK family members.
  • The optimized compound showed potent cellular effects, supporting its therapeutic potential.

Conclusions:

  • Compound 22 represents a promising lead candidate for developing selective CDK2 inhibitors.
  • The optimized macrocyclic inhibitor holds potential for targeted cancer drug development.
  • Further investigation into compound 22 is warranted for its therapeutic application in CDK2-driven malignancies.
Keywords:
CCNE1 amplificationCyclin-dependent kinase 2MacrocycleMolecular dynamic simulationsSmall molecule inhibitor

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