Modulating Protein-Protein Interactions of the Mitotic Polo-like Kinases to Target Mutant KRAS

Cell Chem Biol. 2017 Aug 17;24(8):1017-1028.e7. doi: 10.1016/j.chembiol.2017.07.009. Epub 2017 Aug 10.


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.

Keywords: PLK1; PLK4; PPI inhibitor; Polo-box domain; Polo-like kinase; c-MET; cancer therapy; mutant KRAS; protein-protein interactions.

MeSH terms

  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism*
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Humans
  • Mitosis
  • Molecular Structure
  • Mutation*
  • Protein Binding
  • Protein Interaction Domains and Motifs / drug effects*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Structure-Activity Relationship
  • Substrate Specificity


  • Cell Cycle Proteins
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • PLK4 protein, human
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1
  • Proto-Oncogene Proteins p21(ras)