Development of a Novel Cell-Permeable Protein-Protein Interaction Inhibitor for the Polo-box Domain of Polo-like
David J Huggins1,2,3, Bryn S Hardwick1, Pooja Sharma1
1Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 2XZ, United Kingdom.
Abstract:
Polo-like kinase 1 (PLK1) is a key regulator of mitosis and a recognized drug target for cancer therapy. Inhibiting the polo-box domain of PLK1 offers potential advantages of increased selectivity and subsequently reduced toxicity compared with targeting the kinase domain. However, many if not all existing polo-box domain inhibitors have been shown to be unsuitable for further development. In this paper, we describe a novel compound series, which inhibits the protein-protein interactions of PLK1 via the polo-box domain. We combine high throughput screening with molecular modeling and computer-aided design, synthetic chemistry, and cell biology to address some of the common problems with protein-protein interaction inhibitors, such as solubility and potency. We use molecular modeling to improve the solubility of a hit series with initially poor physicochemical properties, enabling biophysical and biochemical characterization. We isolate and characterize enantiomers to improve potency and demonstrate on-target activity in both cell-free and cell-based assays, entirely consistent with the proposed binding model. The resulting compound series represents a promising starting point for further progression along the drug discovery pipeline and a new tool compound to study kinase-independent PLK functions.
Insights
Researchers developed novel compounds targeting the polo-box domain of Polo-like kinase 1 (PLK1) to inhibit protein-protein interactions. This approach offers a promising strategy for cancer therapy with potentially reduced toxicity.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Polo-like kinase 1 (PLK1) is a critical regulator of cell division (mitosis).
- Targeting PLK1 is a validated strategy for cancer treatment.
- Inhibiting the PLK1 polo-box domain offers greater selectivity and lower toxicity than targeting the kinase domain.
Purpose of the Study:
- To develop novel inhibitors targeting the PLK1 polo-box domain (PBD) for protein-protein interaction inhibition.
- To overcome common challenges with protein-protein interaction inhibitors, such as poor solubility and potency.
- To provide a new tool compound for studying PLK1's kinase-independent functions.
Main Methods:
- High-throughput screening (HTS) to identify initial hit compounds.
- Molecular modeling and computer-aided design (CAD) to optimize compound properties.
- Synthetic chemistry for compound synthesis and modification.
- Biophysical and cell-based assays to assess compound activity and mechanism.
Main Results:
- A novel series of PLK1 PBD inhibitors was identified and optimized.
- Molecular modeling successfully improved the solubility of initial hits.
- Enantiomer isolation enhanced compound potency, demonstrating on-target activity.
- Compounds showed efficacy in both cell-free and cell-based experimental systems.
Conclusions:
- The developed compound series is a promising starting point for further drug discovery and development.
- These novel inhibitors represent valuable tools for investigating PLK1's role beyond its kinase activity.
- Targeting PLK1 PBD interactions offers a viable strategy for developing selective anti-cancer therapeutics.
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