MDM2 inhibitors for cancer therapy

Trends Mol Med. 2007 Jan;13(1):23-31. doi: 10.1016/j.molmed.2006.11.002. Epub 2006 Nov 28.

Abstract

The tumor suppressor p53 is a powerful antitumoral molecule frequently inactivated by mutations or deletions in cancer. However, half of all human tumors express wild-type p53, and its activation by antagonizing its negative regulator murine double minute 2 (MDM2) might offer a new therapeutic strategy. Proof-of-concept experiments have demonstrated the feasibility of this approach in vitro but the development of pharmacological inhibitors has been challenging. Recently, potent and selective small-molecule MDM2 inhibitors have been identified. Studies with these compounds have strengthened the concept that selective, non-genotoxic p53 activation is a viable alternative to current cytotoxic chemotherapy but clinical validation is still pending. Here, the new developments in the quest for pharmacological p53 activators are reviewed with an emphasis on small-molecule inhibitors of the p53-MDM2 interaction.

Publication types

  • Review

MeSH terms

  • Benzodiazepines / chemistry
  • Benzodiazepines / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Imidazoles / chemistry
  • Imidazoles / metabolism
  • Models, Biological*
  • Models, Molecular*
  • Molecular Structure
  • Neoplasms / drug therapy*
  • Oligonucleotides, Antisense / metabolism
  • Oligonucleotides, Antisense / pharmacology
  • Piperazines / chemistry
  • Piperazines / metabolism
  • Protein Binding
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Spiro Compounds / chemistry
  • Spiro Compounds / metabolism
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Imidazoles
  • Oligonucleotides, Antisense
  • Piperazines
  • Spiro Compounds
  • Tumor Suppressor Protein p53
  • Benzodiazepines
  • nutlin 3
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Ubiquitin-Protein Ligases