Targeting MDM2-p53 Interaction for Cancer Therapy: Are We There Yet?
S. Nag, X. Zhang, K.S. Srivenugopal, M.-H. Wang, W. Wang and R. Zhang
Affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 S Coulter Street, Amarillo, TX 79106, USA.
Keywords: Drug target, MDM2, p53, MDM2-p53 interaction, small molecule inhibitor.
Inactivation of the tumor suppressor p53 and/or overexpression of the oncogene MDM2 frequently occur in
human cancers, and are associated with poor prognosis, advanced forms of the disease, and chemoresistance. MDM2, the
major negative regulator of p53, induces p53 degradation and inactivates its tumor suppressing activity. In turn, p53 regulates
MDM2 expression. This MDM2-p53 negative feedback loop has been widely studied and presents an attractive target
for cancer therapy, with a few of the inhibitors of this interaction already having advanced into clinical trials. Additionally,
there is an increasing interest in understanding MDM2’s p53-independent activities in carcinogenesis and cancer
progression, which may also have implications for cancer therapy. This review aims to highlight the various roles that the
MDM2-p53 interaction plays in cancer, the p53 independent oncogenic activities of MDM2 and the various strategies that
may be used to target MDM2 and the MDM2-p53 interaction. We will summarize the major preclinical and clinical evidences
of MDM2 inhibitors for human cancer treatment and make suggestions to further improve efficacy and safety of
this interesting class of cancer therapeutics.
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