The p53 protein respond to a variety of stresses and trigger cell cycle arrest, apoptosis or senescence, thereby protecting against malignant transformation. Almost all of human tumors are believed to harbor a disabled p53, either through mutation of the p53 gene or through aberrant expression of proteins acting as its negative regulators such as Mdm2 or more recently discovered Mdm4. Thus designing molecules to block the MDM2-p53 interaction and reactivate the p53 function has been perceived as a promising therapeutic strategy for the treatment of cancers retaining wild-type p53.

Mdm2 and Mdm4 are closely related, and despite of p53 binding site within Mdm2 and Mdm4 are almost the same, known small-molecule Mdm2 inhibitors like Nutlin-3 are not effective against Mdm4. As a result, their activity is compromised in tumor cells over-expressing Mdm4, preventing these compounds from rescuing the p53 activity.

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