Related Experiment Video

Updated: Apr 23, 2026

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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Structure-based design of potent pyrazolo[1,5-a]pyrimidine CDK4/6 inhibitors: biological evaluation and computational

Faizah A Binjubair1, Mahmoud S Elkotamy2, Amr A Mattar3

  • 1Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University P.O. Box 2457 Riyadh 11451 Saudi Arabia.

RSC Medicinal Chemistry
|April 22, 2026
PubMed

Insights

Researchers developed novel pyrazolo[1,5-a]pyrimidine compounds targeting cyclin-dependent kinases (CDKs) for cancer therapy. Compound 19i showed significant antiproliferative effects and induced apoptosis in colorectal cancer cells by inhibiting CDK4 and CDK6.

Area of Science:

  • Medicinal Chemistry
  • Molecular Biology
  • Oncology

Background:

  • Cyclin-dependent kinases (CDKs) dysregulation promotes cancer by driving uncontrolled cell division.
  • CDK4 and CDK6 are critical regulators of the cell cycle and represent key therapeutic targets in oncology.

Purpose of the Study:

  • To design, synthesize, and evaluate novel pyrazolo[1,5-a]pyrimidine derivatives as potent inhibitors of CDK4 and CDK6.
  • To identify lead compounds with significant antiproliferative activity against colorectal cancer cells.

Main Methods:

  • Synthesis and structural characterization of fifteen pyrazolo[1,5-a]pyrimidine derivatives.
  • In vitro antiproliferative assays using HCT-116 colorectal cancer cells.
  • Cell cycle analysis, apoptosis assays (ELISA), and Western blotting.
  • Biochemical kinase inhibition assays for CDK4 and CDK6.
  • Molecular docking and molecular dynamics simulations.

Main Results:

  • Compound 19i demonstrated potent antiproliferative efficacy against HCT-116 cells (IC50 = 1.02 μM), comparable to doxorubicin.
  • 19i induced significant G0/G1 cell cycle arrest and apoptosis (47.76%), activating the p53-dependent intrinsic pathway.
  • Significant inhibition of CDK4 (IC50 = 0.087 μM) and CDK6 (IC50 = 0.114 μM) was observed.
  • Molecular modeling confirmed favorable binding interactions and stability of compound 19i with CDK4/6.

Conclusions:

  • The pyrazolo[1,5-a]pyrimidine scaffold is a promising framework for developing novel CDK inhibitors.
  • Compound 19i represents a potential lead candidate for targeted anticancer therapies, particularly for colorectal cancer.
  • Further optimization of this scaffold could lead to more effective CDK-targeted cancer treatments.

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