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The p53 tumor suppressor is controlled by MDM2, which binds p53 and negatively regulates its transcriptional activity and stability. Many tumors overproduce MDM2 to impair p53 function. Therefore, restoration of p53 activity by inhibiting the p53–MDM2 binding represents an attractive novel approach to cancer therapy. Recently developed potent and selective small-molecule antagonists of the p53–MDM2 interaction have been used to demonstrate the proof-of-concept for this approach. These compounds interact specifically with the p53-binding pocket of MDM2 and release p53 from negative control. Treatment of cancer cells expressing wild-type p53 stabilize p53 and activate the p53 pathway, leading to cell cycle arrest and apoptosis. In mice-bearing established human tumor xenografts, MDM2 antagonists caused tumor inhibition and regression at nontoxic concentrations, suggesting that they may have a therapeutic utility in the treatment of cancer. An increasing number of MDM2 antagonists are being generated and some of them have entered clinical trials. Here, we review this class of emerging drugs with an emphasis on small molecules that inhibit the p53–MDM2 interaction. [ABSTRACT FROM AUTHOR]

MDM2 is an oncogene that is frequently over-expressed in various human cancers, including sarcomas, gliomas, melanomas, and breast cancers.1 The primary function of MDM2 is to inhibit the activity of the p53 tumor suppressor protein. P53 inhibits cell proliferation in response to DNA damage and other stresses by activating the transcription of genes that mediate either cell-cycle arrest or apoptosis. MDM2 binds the transactivation domain of p53 and inhibits the ability of p53 to activate transcription. Importantly, MDM2 binding also promotes the ubiquitin-mediated degradation of p53, as well as the export of p53 from the nucleus to the cytoplasm. The MDM2 gene itself is transcriptionally activated by p53, thus forming an autoregulatory feedback loop in which p53 promotes the expression of its own inhibitory factor. The ability of MDM2 to promote the degradation and nuclear export of p53 depends on an intact RING finger domain located in the MDM2 C terminus. This chapter will discuss the mechanisms by which MDM2 inhibits p53 function, with an emphasis on the requirement of the MDM2 RING finger domain in p53 inhibition. [ABSTRACT FROM AUTHOR]