Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy

Annu Rev Pharmacol Toxicol. 2009;49:223-41. doi: 10.1146/annurev.pharmtox.48.113006.094723.

Abstract

Tumor suppressor p53 is an attractive cancer therapeutic target because it can be functionally activated to eradicate tumors. Direct gene alterations in p53 or interaction between p53 and MDM2 proteins are two alternative mechanisms for the inactivation of p53 function. Designing small molecules to block the MDM2-p53 interaction and reactivate the p53 function is a promising therapeutic strategy for the treatment of cancers retaining wild-type p53. This review will highlight recent advances in the design and development of small-molecule inhibitors of the MDM2-p53 interaction as new cancer therapies. A number of these small-molecule inhibitors, such as analogs of MI-219 and Nutlin-3, have progressed to advanced preclinical development or early phase clinical trials.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Cell Cycle Proteins
  • Clinical Trials as Topic
  • Drug Design
  • Drug Evaluation, Preclinical
  • Humans
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use
  • Neoplasms / drug therapy*
  • Nuclear Proteins / antagonists & inhibitors*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Piperazines / therapeutic use
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Imidazoles
  • MDM4 protein, human
  • Nuclear Proteins
  • Piperazines
  • Proto-Oncogene Proteins
  • Tumor Suppressor Protein p53
  • nutlin 3
  • Proto-Oncogene Proteins c-mdm2