A small molecule inhibitor of p53-inducible protein phosphatase PPM1D

Bioorg Med Chem Lett. 2012 Jan 1;22(1):729-32. doi: 10.1016/j.bmcl.2011.10.084. Epub 2011 Oct 31.

Abstract

PPM1D is a p53-inducible Ser/Thr protein phosphatase. PPM1D gene amplification and overexpression have been reported in a variety of human tumors, including breast cancer and neuroblastoma. Because the phosphatase activity of PPM1D is essential for its oncogenic role, PPM1D inhibitors should be viable anti-cancer agents. In our current study, we showed that SPI-001 was a potent and specific PPM1D inhibitor. SPI-001 inhibited PPM1D phosphatase activity in PPM1D-overexpressing human breast cancer cells and increased phosphorylation of p53. Furthermore, SPI-001 suppressed cell proliferation by inducing apoptosis. Our present study suggested that SPI-001 was a potential lead compound in developing anti-cancer drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Humans
  • Indoles / pharmacology
  • Inhibitory Concentration 50
  • Models, Chemical
  • Neoplasms / drug therapy*
  • Phenanthrenes / pharmacology*
  • Phosphoprotein Phosphatases / antagonists & inhibitors*
  • Phosphoric Monoester Hydrolases / chemistry
  • Phosphorylation
  • Protein Phosphatase 2C
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins pp60(c-src) / metabolism
  • Time Factors
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Indoles
  • Phenanthrenes
  • SPI-001
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • DAPI
  • MATK protein, human
  • Proto-Oncogene Proteins pp60(c-src)
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases
  • PPM1D protein, human
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2C
  • Phosphoric Monoester Hydrolases