Probing cell-division phenotype space and Polo-like kinase function using small molecules

Nat Chem Biol. 2006 Nov;2(11):618-26. doi: 10.1038/nchembio826. Epub 2006 Oct 8.

Abstract

Cell-permeable small molecules that inhibit their targets on fast timescales are powerful probes of cell-division mechanisms. Such inhibitors have been identified using phenotype-based screens with chemical libraries. However, the characteristics of compound libraries needed to effectively span cell-division phenotype space, to find probes that target different mechanisms, are not known. Here we show that a small collection of 100 diaminopyrimidines (DAPs) yields a range of cell-division phenotypes, including changes in spindle geometry, chromosome positioning and mitotic index. Monopolar mitotic spindles are induced by four inhibitors, including one that targets Polo-like kinases (Plks), evolutionarily conserved serine/threonine kinases. Using chemical inhibitors and high-resolution live-cell microscopy, we found that Plk activity is needed for the assembly and maintenance of bipolar mitotic spindles. Plk inhibition destabilizes kinetochore microtubules while stabilizing other spindle microtubules, leading to monopolar spindles. Further testing of compounds based on 'privileged scaffolds', such as the DAP scaffold, could lead to new cell-division probes and antimitotic agents.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Benzothiazoles / chemistry
  • Benzothiazoles / pharmacology*
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / physiology*
  • Cell Division / drug effects
  • Cell Division / physiology
  • Cell Line
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Haplorhini
  • Humans
  • Microtubules / drug effects
  • Microtubules / metabolism
  • Phenotype
  • Phenylenediamines / chemistry
  • Phenylenediamines / pharmacology*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / physiology*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • RNA Interference
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • Sensitivity and Specificity
  • Spindle Apparatus / drug effects
  • Spindle Apparatus / genetics
  • Spindle Apparatus / metabolism
  • Structure-Activity Relationship
  • Time Factors
  • Tubulin / drug effects
  • Tubulin / genetics
  • Tubulin / metabolism
  • Xenopus Proteins / antagonists & inhibitors*
  • Xenopus Proteins / physiology*
  • Xenopus laevis / metabolism

Substances

  • 2-(4-acetamidylphenylamino)-4-(2-benzoylphenylamino)-5-nitropyrimidine
  • 2-(benzothiazol-6-ylamino)-4-(indan-5-ylamino)pyrimidine
  • Benzothiazoles
  • Cell Cycle Proteins
  • Phenylenediamines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Recombinant Proteins
  • Tubulin
  • Xenopus Proteins
  • Plk1 protein, Xenopus
  • Protein-Serine-Threonine Kinases

Associated data

  • PubChem-Substance/14717149
  • PubChem-Substance/14717150
  • PubChem-Substance/14717151
  • PubChem-Substance/14717152
  • PubChem-Substance/14717153
  • PubChem-Substance/14717154
  • PubChem-Substance/14717155
  • PubChem-Substance/14717156
  • PubChem-Substance/14717157
  • PubChem-Substance/14717158