Structure-Guided Discovery of Selective Polo-Like Kinase 3 Inhibitors

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• Polo-like kinases (PLKs) are crucial serine/threonine kinases regulating cell cycle and proliferation.
• While PLK1 inhibitors show oncology potential, other PLKs' functions remain unclear due to a lack of selective inhibitors.
• Selective chemical probes are needed to investigate the diverse biological roles of PLK family members.

Purpose of the Study:

• To discover potent and selective Polo-like kinase 3 (PLK3) inhibitors.
• To develop chemical probes for elucidating PLK biology.
• To explore the relationship between PLK isoform inhibition and toxicity.

Main Methods:

• Utilized computational tools to identify distinct pharmacophore features in homologous PLK binding sites.
• Employed parallel medicinal chemistry (PMC) starting from high-throughput screening hits.
• Performed structure-assisted drug discovery and compound profiling across various PLK selectivities.

Main Results:

• Successfully identified potent and selective PLK3 inhibitors with favorable drug-like properties.
• Developed selective chemical probes enabling further investigation into PLK functions.
• Established a correlation between specific PLK isoform inhibition and observed toxicities.

Conclusions:

• Medicinal chemistry and computational approaches can yield selective inhibitors for challenging targets like PLK3.
• The developed PLK3 inhibitors serve as valuable tools for biological research.
• Understanding isoform-specific inhibition is critical for predicting and mitigating potential toxicities in drug development.