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Updated: Jul 9, 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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Exploring cyclin-dependent kinase inhibitors: a comprehensive study in search of CDK-6 inhibitors using a

Bharath Kumar Chagaleti1, Venkatesan Saravanan1, Chitra Vellapandian2

  • 1Department of Pharmaceutical Chemistry, SRM College of Pharmacy, SRM Institute of Science and Technology Kattankulathur-603203 India kathirak@srmist.edu.in drmkkathir@gmail.com.

RSC Advances
|November 29, 2023
PubMed

Insights

Researchers developed novel pyrazolopyrimidine fused azetidinones to target cyclin-dependent kinase 6 (CDK-6) for cancer therapy. Computational studies identified promising compounds with favorable binding and stability, offering potential new cancer treatments.

Area of Science:

  • Medicinal Chemistry
  • Computational Chemistry
  • Oncology

Background:

  • Cancer remains a global health challenge, with drug resistance a significant issue.
  • Targeting cyclin-dependent kinases (CDKs), particularly CDK-6, is a promising strategy for inhibiting cancer cell proliferation.
  • Novel therapeutic agents are needed to overcome resistance and improve cancer treatment outcomes.

Purpose of the Study:

  • To design and computationally evaluate novel pyrazolopyrimidine fused azetidinones as potential inhibitors of CDK-6.
  • To explore the potential of molecular hybridization in developing targeted cancer therapeutics.
  • To identify lead compounds with favorable pharmacokinetic and binding properties for CDK-6 inhibition.

Main Methods:

  • Ligand-based pharmacophore modeling to define key interaction features.
  • In silico pharmacokinetic (ADMET) profiling for drug-likeness assessment.
  • Molecular docking and molecular dynamics simulations to evaluate binding affinity and complex stability.

Main Results:

  • Identified 18 promising pyrazolopyrimidine fused azetidinone derivatives targeting CDK-6.
  • Pharmacophore model revealed essential aromatic hydrophobic and hydrogen bond acceptor features.
  • Docking studies showed strong binding energies (-6.5 to -8.0 kcal mol⁻¹) and favorable interactions.
  • Compounds B6 and B18 exhibited excellent stability and binding profiles in molecular dynamics simulations.
  • Designed compounds demonstrated good predicted ADMET properties.

Conclusions:

  • Novel pyrazolopyrimidine fused azetidinones show significant potential as CDK-6 inhibitors.
  • Computational methods successfully guided the design of effective anti-cancer lead compounds.
  • These compounds represent promising candidates for further development in cancer therapy, potentially overcoming existing resistance mechanisms.

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