Expanding the horizon of chemotherapeutic targets: From MDM2 to MDMX (MDM4)

Alterations of p53 signalling pathway is the most frequent event in human cancers. About 50% of these, albeit showing wild-type p53, have flaws in the control mechanisms of p53 levels and activity. MDM2 and MDMX (MDM4) are the main negative regulators of p53. The relevance of MDM2 on the regulation of p53 levels and activity has fostered the development of strategies aimed at restoring p53 functions by blocking the physical interaction between MDM2 and p53. As a consequence, a number of different small molecules and peptidomimetics have been disclosed in the last decade as inhibitors of MDM2/p53 interaction. Recent studies, however, have thrust MDMX into the limelight as an additional chemotherapeutic target, suggesting the presence of a more complex relationship between MDM2, MDMX and p53. In this review article, we report key aspects of MDMX-mediated regulation of p53, recent advances in the structural characterization of the protein, and the progress made so far in the medicinal chemistry of MDMX ligands.