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Harnessing Structure Prediction of Polo-Like Kinase 4 for Drug Repurposing

Harshita Kasera1, Priyanka Singh1

  • 1Department of Bioscience & Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, India.

Cytoskeleton (Hoboken, N.J.)
|March 20, 2025
PubMed

Insights

Researchers identified Alectinib as a potential drug targeting Polo-like kinase 4 (PLK4) by focusing on its unique polo-box domain (PBD). This offers a more specific approach for cancer therapies by repurposing existing chemical scaffolds.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Cancer Biology

Background:

  • Polo-like kinase 4 (PLK4) is a key centrosome regulator with aberrant expression in various cancers.
  • Current PLK4 inhibitors target the kinase domain, risking off-target effects due to structural similarities with other kinases.
  • Targeting the unique C-terminal polo-box domain (PBD) of PLK4 offers a strategy for enhanced drug specificity.

Purpose of the Study:

  • To predict the full-length structure of human PLK4.
  • To virtually screen chemical libraries for compounds targeting unique PLK4 regions, particularly the PBD.
  • To identify novel therapeutic scaffolds for PLK4-driven cancers.

Main Methods:

  • Utilized ab initio and threading approaches for full-length human PLK4 structure prediction.
  • Performed virtual screening of the ChEMBL library against the predicted PLK4 structure.
  • Employed FT-IR analysis to confirm drug-target interactions.

Main Results:

  • Successfully predicted the full-length structure of human PLK4.
  • Identified Alectinib as a hit compound targeting unique regions of PLK4.
  • Observed that Alectinib affects centrosome numbers in correlation with PLK4 levels.
  • FT-IR confirmed Alectinib's interaction with the PLK4 PBD.

Conclusions:

  • Alectinib demonstrates potential as a therapeutic agent targeting the unique PBD of PLK4.
  • This study identifies a chemical scaffold that can be repurposed for developing specific PLK4 inhibitors.
  • The findings pave the way for more targeted cancer therapies by exploiting PLK4's unique structural features.
Keywords:
AlectinibPLK4centrinonecentrosomekinasepolo‐box

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