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

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.