The past, present and future of potential small-molecule drugs targeting p53-MDM2/MDMX for cancer therapy

The p53 gene, a well-known tumor suppressor gene, plays a crucial role in cell cycle regulation, DNA repair, cell differentiation, and apoptosis. MDM2 exerts p53-dependent activity mainly by binding to p53 protein to form MDM2-p53 negative feedback loop. In addition, MDM2 is involved in a number of pathways that regulate cell proliferation and apoptosis, playing a p53-independent role. The p53 binding domain of MDMX bind to p53 transcriptional activation domain, inhibiting the transcriptional activity of p53 on its downstream genes, but does not mediate the degradation of p53. The anti-tumor effect is exerted by inhibiting the interaction between the MDM2/MDMX protein and the p53 protein by a small-molecule or by restoring the activity of the p53 protein. This review describes in the structural features, biological functions and mechanisms of p53-MDM2/MDMX, and summarizes small-molecule targeting p53-MDM2/MDMX.