P53 and Mdm2 Antagonists As Novel Targets for Human Cancer Therapy

Abstract

p53 is an attractive target for therapeutic design because ofits involvement as a mediator of growth arrest andapoptosis after exposure to chemoradiotherapy and / orradiotherapy. p53 is activated in response to oncogenicand other cellular stress and induces up or downregulationof a variety of genes involved in cell cycle arrest, DNArepair, senescence or apoptosis. In a tightly controlledfeedback loop p53 also induces expression of itsdownregulators, such as E3 ubiquitin ligases such asMDM2 (murine double minute 2) which binds to p53 andpromotes its ubiquitination followed by nuclear exportand proteosomal degradation. This process together withother ubiquitin ligases keeps cellular p53 levelsconstitutively low. MDM2 is highly overexpressed inmany tumors which effectively abolishes p53 functions.MDM2 antagonists are therefore, attractive anticancerdrugs. Nutilins disrupts p53-MDM2 interaction bycompeting with p53 for MDM2 by binding to hydrophobicp53 binding pocket in the N-terminal domain of MDM2.Blocking the MDM2-p53 interaction to reactivate the p53function is a promising cancer therapeutic strategy.Restoration of p53 transcriptional responses in p53deficient cells may provide a functional means to developanticancer therapeutics. This review will highlight the roleof small-molecule inhibitors of the MDM2-p53interaction as a cancer therapeutic approach.Keywords: p53/ MDM2 antagonists, Cancer