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Updated: May 25, 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

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CADD-based discovery of novel heterocyclic pyrimidine-based CDK4/6 inhibitors: Design, synthesis, and anti-breast

Xinya Lv1, Xiaoling Huang1, Lulu Tian1

  • 1Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, China.

European Journal of Medicinal Chemistry
|May 23, 2026
PubMed

Insights

Researchers developed novel cyclin-dependent kinase 4/6 (CDK4/6) inhibitors for breast cancer treatment. Compound 3c showed potent CDK4/6 inhibition, reduced tumor growth in vivo, and arrested cell cycle, indicating therapeutic potential.

Area of Science:

  • Medicinal Chemistry
  • Molecular Biology
  • Oncology

Background:

  • Cyclin-dependent kinase 4/6 (CDK4/6) dysregulation is crucial in breast cancer progression.
  • Existing CDK4/6 inhibitors have limitations, necessitating novel therapeutic agents.

Purpose of the Study:

  • To design, synthesize, and evaluate novel CDK4/6 inhibitors for breast cancer therapy.
  • To identify potent and selective CDK4/6 inhibitors using computer-aided drug design.

Main Methods:

  • Employed computer-aided drug design (CADD) with pyridine-2-aminopyrimidine, thieno[3,2-d]pyrimidine, and pyrazolo[1,5-a]pyrimidine scaffolds.
  • Synthesized 40 potential inhibitors and screened them using molecular docking and binding free energy calculations.
  • Validated inhibitory activity, selectivity, cell cycle arrest, apoptosis induction, and in vivo efficacy in a xenograft model.

Main Results:

  • Compound 3c demonstrated potent CDK4/6 inhibition in breast cancer cell lines (IC50s 0.11-0.21 μM).
  • Compound 3c exhibited selectivity against 23 kinases and inhibited cell colony formation and migration.
  • In vivo studies showed compound 3c achieved a 45.20% tumor inhibition rate in an MCF-7 xenograft model.

Conclusions:

  • Compound 3c is a promising novel CDK4/6 inhibitor with significant therapeutic potential for breast cancer.
  • The study highlights the efficacy of CADD strategies in discovering novel anticancer agents.
Keywords:
Antitumor activityBreast cancerCADD strategyCDK4/6 inhibitorHeterocyclic pyrimidine structure

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