MDM2 inhibitors for cancer therapy

• Published in: Trends in molecular medicine 2007-01, Vol.13 (1), p.23-31
• Main Author: Vassilev, Lyubomir T
• Format: Article
• Language: English
• Subjects: 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; Pathology; 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
• ISSN: 1471-4914; 1471-499X
• DOI: 10.1016/j.molmed.2006.11.002

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.