Modulating Protein-Protein Interactions of the Mitotic Polo-like Kinases to Target Mutant KRAS. Academic Article uri icon

Overview

abstract

  • Mutations activating KRAS underlie many forms of cancer, but are refractory to therapeutic targeting. Here, we develop Poloppin, an inhibitor of protein-protein interactions via the Polo-box domain (PBD) of the mitotic Polo-like kinases (PLKs), in monotherapeutic and combination strategies to target mutant KRAS. Poloppin engages its targets in biochemical and cellular assays, triggering mitotic arrest with defective chromosome congression. Poloppin kills cells expressing mutant KRAS, selectively enhancing death in mitosis. PLK1 or PLK4 depletion recapitulates these cellular effects, as does PBD overexpression, corroborating Poloppin's mechanism of action. An optimized analog with favorable pharmacokinetics, Poloppin-II, is effective against KRAS-expressing cancer xenografts. Poloppin resistance develops less readily than to an ATP-competitive PLK1 inhibitor; moreover, cross-sensitivity persists. Poloppin sensitizes mutant KRAS-expressing cells to clinical inhibitors of c-MET, opening opportunities for combination therapy. Our findings exemplify the utility of small molecules modulating the protein-protein interactions of PLKs to therapeutically target mutant KRAS-expressing cancers.

publication date

  • August 10, 2017

Research

keywords

  • Cell Cycle Proteins
  • Mutation
  • Protein Interaction Domains and Motifs
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins p21(ras)

Identity

PubMed Central ID

  • PMC5563081

Scopus Document Identifier

  • 85027513025

Digital Object Identifier (DOI)

  • 10.1016/j.chembiol.2017.07.009

PubMed ID

  • 28807782

Additional Document Info

volume

  • 24

issue

  • 8