Development of a Novel Cell-Permeable Protein-Protein Interaction Inhibitor for the Polo-box Domain of Polo-like Kinase 1. Academic Article uri icon

Overview

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.

authors

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

publication date

  • December 24, 2019

Identity

PubMed Central ID

  • PMC6964520

Scopus Document Identifier

  • 33746872935

Digital Object Identifier (DOI)

  • 10.1021/jm060522a

PubMed ID

  • 31956833

Additional Document Info

volume

  • 5

issue

  • 1