Inhibition of the p53-MDM2 interaction: targeting a protein-protein interface.
MDM2 inhibits p53 transcriptional activity, favors its nuclear export, and stimulates its degradation. Inhibition of the p53-MDM2 interaction with synthetic molecules should therefore lead to both the nuclear accumulation and the activation of p53 followed by the death of the tumor cells from apoptosis. Inhibitors of the p53-MDM2 interaction might be attractive new anticancer agents that could be used to activate wild-type p53 in tumors. This review describes our current knowledge on the properties of the existing p53-MDM2 antagonists. Because the discovery of modulators of protein-protein interactions is an emerging field in drug discovery, the strategy used for designing inhibitors of the p53-MDM2 interaction could serve as an example for other protein interfaces.
Chène
Patrick
P
Oncology Department, Novartis, K125 443, CH-4002 Basel, Switzerland. patrick_chene@yahoo.com
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2