Targeting the PPM1D phenotype; 2,4-bisarylthiazoles cause highly selective apoptosis in PPM1D amplified cell-lines

Bioorg Med Chem Lett. 2014 Aug 1;24(15):3469-74. doi: 10.1016/j.bmcl.2014.05.067. Epub 2014 May 29.


The metal-dependent phosphatase PPM1D (WIP1) is an important oncogene in cancer, with over-expression of the protein being associated with significantly worse clinical outcomes. In this communication we describe the discovery and optimization of novel 2,4-bisarylthiazoles that phenocopy the knockdown of PPM1D, without inhibiting its phosphatase activity. These compounds cause growth inhibition at nanomolar concentrations, induce apoptosis, activate p53 and display impressive cell-line selectivity. The results demonstrate the potential for targeting phenotypes in drug discovery when tackling challenging targets or unknown mechanisms.

Keywords: 2,4-Bisarylthiazole; Apoptosis; PPM1D; Phenotype; p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Phenotype
  • Phosphoprotein Phosphatases / antagonists & inhibitors*
  • Phosphoprotein Phosphatases / metabolism
  • Protein Phosphatase 2C
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*
  • Tumor Suppressor Protein p53 / metabolism


  • Antineoplastic Agents
  • Thiazoles
  • Tumor Suppressor Protein p53
  • PPM1D protein, human
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2C