The tumor suppressor protein p53 is inactivated in all types of human cancers, either by
negative regulation, by mutation or deletion of its gene. Specifically, in tumors that retain wild-type
(wt) p53 status, p53 is inactivated by interaction with negative regulators, such as MDM2 and MDMX.
These two proteins are found to be overexpressed in several different types of cancers, and the restoration
of p53 activity by inhibition of these proteins is now considered an important approach for cancer
treatment. The first studies using this strategy to reactivate wt p53 were focused on the development of
small molecules that could inhibit MDM2. In this way, p53 could be liberated and act again as a tumor
suppressor. From these studies, nine small molecules have reached clinical trials. More recently,
MDMX was also identified as an important therapeutic target to efficiently reactivate wt p53, and it is
now considered that, for full p53 reactivation, dual inhibition of MDM2 and MDMX is required. In this
review we will focus on the most recent advances in the discovery of novel small molecules and stapled
peptides that act as selective MDMX inhibitors or as dual MDM2/X inhibitors.