Development of a Novel Cell-Permeable Protein-Protein Interaction Inhibitor for the Polo-box Domain of Polo-like Kinase 1

David J. Huggins, Bryn S. Hardwick, Pooja Sharma, Amy Emery, Luca Laraia, Fengzhi Zhang, Ana J. Narvaez, Meredith Roberts-Thomson, Alex T. Crooks, Robert G. Boyle, Richard Boyce, David W. Walker, Natalia Mateu, Grahame J. McKenzie, David R. Spring, Ashok R. Venkitaraman*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

162 Downloads (Pure)


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.
Original languageEnglish
JournalACS Omega
Issue number1
Pages (from-to)822-831
Publication statusPublished - 2020


  • Assays
  • Inhibitors
  • Inhibition
  • Peptides and proteins Solutbility


Dive into the research topics of 'Development of a Novel Cell-Permeable Protein-Protein Interaction Inhibitor for the Polo-box Domain of Polo-like Kinase 1'. Together they form a unique fingerprint.

Cite this