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Related Experiment Video

Updated: Oct 30, 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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Nonpeptidic, Polo-Box Domain-Targeted Inhibitors of PLK1 Block Kinase Activity, Induce Its Degradation and

Danda Chapagai1, Gurusankar Ramamoorthy1, Jessy Varghese1

  • 1Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, United States.

Journal of Medicinal Chemistry
|July 2, 2021
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Summary

Novel nonpeptidic inhibitors, abbapolins, target the polo-box domain of polo-like kinase 1 (PLK1). Abbapolins show potent antiproliferative effects, even in resistant cancer cells.

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Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Polo-like kinase 1 (PLK1) is crucial for cell division (mitosis).
  • Targeting PLK1's polo-box domain (PBD) offers an alternative to ATP-competitive inhibitors, circumventing resistance and off-target effects.
  • Developing novel PLK1 inhibitors is essential for cancer therapy.

Purpose of the Study:

  • To identify and characterize novel nonpeptidic inhibitors targeting the PLK1 PBD.
  • To evaluate the antiproliferative activity and specificity of these novel inhibitors, termed abbapolins.
  • To investigate the mechanism of action of abbapolins, including PLK1 engagement and degradation.

Main Methods:

  • Utilized the REPLACE strategy for inhibitor discovery.
  • Assessed antiproliferative activity in prostate tumor and other cell lines.
  • Employed cellular thermal shift assay (CETSA) to confirm PLK1 binding.
  • Measured TCTP phosphorylation to evaluate PLK1 kinase inhibition.
  • Monitored PLK1 degradation as a marker of target engagement.

Main Results:

  • Identified novel nonpeptidic PBD-binding inhibitors (abbapolins).
  • Abbapolins demonstrated potent antiproliferative activity across various cell lines, including resistant models.
  • Abbapolins exhibited PLK1-specific binding and inhibited PLK1 kinase activity by blocking TCTP phosphorylation.
  • Abbapolins induced PLK1 degradation, correlating with antiproliferative effects.

Conclusions:

  • Abbapolins represent a promising new class of nonpeptidic PLK1 PBD inhibitors.
  • These compounds display potent and specific anticancer activity, overcoming resistance to existing therapies.
  • Abbapolins offer a viable therapeutic strategy targeting PLK1, with a unique mechanism involving target degradation.