MDM2 suppresses c-Myc synthesis by binding to the 5’ mRNA translation regulatory sequence.

MDM2 is a key negative regulator of p53 and a target for emerging cancer therapies designed to activate p53. Likewise, targeting c-Myc is a longstanding but challenging goal in cancer therapy.

Here we report that the small MDM2 binding drug Milademetan promotes an interaction between MDM2 and the 5’ untranslated region (UTR) of the c-Myc mRNA, causing a suppression of c-Myc mRNA translation without affecting c-Myc RNA levels. The interaction also occurs under non-proliferative conditions in the absence of drug. Milademetan-mediated c-Myc depletion is accompanied by the induction of apoptosis and suppression of cell proliferation and prevents tumor growth, independently of p53 status.