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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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Structure-guided design and development of cyclin-dependent kinase 4/6 inhibitors: A review on therapeutic

Mohd Yousuf1, Manzar Alam2, Anas Shamsi2

  • 1Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, India.

International Journal of Biological Macromolecules
|July 25, 2022
PubMed

Insights

Cyclin-dependent kinase 6 (CDK6) is crucial for cell cycle progression and is implicated in various cancers. CDK4/6 inhibitors show promise as anti-cancer agents by targeting cell cycle regulation, with ongoing research exploring their therapeutic potential and combinations.

Area of Science:

  • Molecular Biology
  • Oncology
  • Pharmacology

Background:

  • Cyclin-dependent kinase 6 (CDK6) regulates cell cycle events and transcriptional processes.
  • Dysregulated CDK6 function is associated with the development and progression of multiple tumor types, making it a significant drug target.
  • CDK4/6 inhibitors have emerged as promising anti-cancer agents due to their role in tumor development.

Purpose of the Study:

  • To review the roles of CDK6 in cancer.
  • To discuss the current status of CDK4/6 inhibitors in cancer therapy.
  • To explore the potential for designing novel anti-cancer agents based on CDK4/6 structural features.

Main Methods:

  • Literature review of CDK6's role in cancer.
  • Analysis of pre-clinical and clinical data for CDK4/6 inhibitors.
  • Discussion of structural implications for drug design.
  • Review of combination therapies involving CDK4/6 inhibitors.

Main Results:

  • CDK4/6 inhibitors prevent Rb phosphorylation and E2F liberation, inhibiting the G1 to S transition.
  • These inhibitors demonstrate potent anti-cancer activity, particularly in HR+/HER2- breast cancer.
  • Abemaciclib, palbociclib, and ribociclib are examples of CDK4/6 inhibitors that control cell cycle, induce senescence, and disrupt tumor cells in pre-clinical studies.

Conclusions:

  • CDK6 plays a critical role in cancer, and CDK4/6 inhibitors represent a significant therapeutic strategy.
  • Available CDK4/6 inhibitors have demonstrated therapeutic potential and limitations that require detailed understanding.
  • Future directions include optimizing existing inhibitors and exploring combination therapies for enhanced cancer management.
Keywords:
CDK4/6 inhibitorsCancer therapyCyclin-dependent kinasesDrug design and developmentRetinoblastomaStructure-based drug design and discovery

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