p53 and MDM2 antagonists: As novel targets for human cancer therapy

p53 is an attractive target for therapeutic design because of its involvement as a mediator of growth arrest and apoptosis after exposure to chemoradiotherapy and /or radiotherapy. p53 is activated in response to oncogenic and other cellular stress and induces up or downregulation of a variety of genes involved in cell cycle arrest, DNA repair, senescence or apoptosis. In a tightly controlled feedback loop p53 also induces expression of its downregulators, such as E3 ubiquitin ligases such as MDM2 (murine double minute 2) which binds to p53 and promotes its ubiquitination followed by nuclear export and proteosomal degradation. This process together with other ubiquitin ligases keeps cellular p53 levels constitutively low. MDM2 is highly overexpressed in many tumors which effectively abolishes p53 functions. MDM2 antagonists are therefore, attractive anticancer drugs. Nutilins disrupts p53-MDM2 interaction by competing with p53 for MDM2 by binding to hydrophobic p53 binding pocket in the N-terminal domain of MDM2. Blocking the MDM2-p53 interaction to reactivate the p53 function is a promising cancer therapeutic strategy. Restoration of p53 transcriptional responses in p53 deficient cells may provide a functional means to develop anticancer therapeutics. This review will highlight the role of small-molecule inhibitors of the MDM2-p53 interaction as a cancer therapeutic approach.