Related Experiment Video

Updated: Jan 9, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

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

Published on: October 26, 2015

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Recent advance in macrocyclic CDK inhibitors

Jiamin Zheng1, Zhisen Zhang1, Jinxin Liu2

  • 1Department of Medicinal Chemistry, Insilico Medicine Shanghai Ltd., Shanghai, China.

Future Medicinal Chemistry
|December 9, 2025
PubMed

Insights

Macrocycles offer a promising strategy to develop novel cyclin-dependent kinase (CDK) inhibitors, potentially overcoming resistance and toxicity issues seen with current cancer therapies.

Area of Science:

  • Medicinal Chemistry
  • Oncology
  • Molecular Biology

Background:

  • Cyclin-dependent kinases (CDKs) are crucial regulators of cell cycle and transcription, making them key targets in cancer therapy.
  • CDK4/6 inhibitors have shown success in breast cancer, but challenges like resistance and off-target toxicity persist.
  • Macrocycle-based drug design is emerging as a strategy to improve kinase inhibitor efficacy and drug-like properties.

Purpose of the Study:

  • To review recent advancements in macrocyclization strategies for developing cyclin-dependent kinase (CDK) inhibitors.
  • To highlight how macrocyclic scaffolds can address limitations of current CDK-targeted therapies.
  • To explore the structural evolution of CDK inhibitors from acyclic to macrocyclic forms.

Main Methods:

  • Literature review of scientific publications and clinical trials from 2015-2025.
  • Analysis of structural modifications in CDK inhibitor design, focusing on macrocyclization techniques.
  • Evaluation of the impact of macrocyclization on kinase inhibitory activity, selectivity, and drug-like properties.

Main Results:

  • Macrocyclization strategies have enhanced the potency and selectivity of CDK inhibitors.
  • Macrocyclic CDK inhibitors show potential in overcoming acquired resistance mechanisms.
  • Improved pharmacokinetic profiles and reduced off-target effects are observed with macrocyclic designs.

Conclusions:

  • Macrocyclization represents a powerful approach for designing next-generation CDK inhibitors.
  • These novel macrocyclic agents hold significant promise for improving cancer treatment outcomes.
  • Further research and clinical evaluation are warranted to fully realize the therapeutic potential of macrocyclic CDK inhibitors.
Keywords:
Drug designcyclin-dependent kinasesdrug discoverymacrocyclesoncological therapeutics

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