Title:Targeting p53-MDM2 Interaction Using Small Molecule Inhibitors and the Challenges Needed to be Addressed
Volume: 20
Issue: 11
Author(s): Maryam Zanjirband*Soheila Rahgozar
Affiliation:
- Department of Cellular and Molecular Biology, Faculty of Science, University of Isfahan, Azadi Square, Isfahan,Iran
Keywords:
MDM2, p53, MDM2-p53 antagonists, p53-independent effects, gene signature, hematotoxicity.
Abstract: MDM2 protein is the core negative regulator of p53 that maintains the cellular levels of p53
at a low level in normal cells. Mutation of the TP53 gene accounts for 50% of all human cancers. In
the remaining malignancies with wild-type TP53, p53 function is inhibited through other mechanisms.
Recently, synthetic small molecule inhibitors have been developed which target a small hydrophobic
pocket on MDM2 to which p53 normally binds. Given that MDM2-p53 antagonists have been undergoing
clinical trials for different types of cancer, this review illustrates different aspects of these new
cancer targeted therapeutic agents with the focus on the major advances in the field. It emphasizes on
the p53 function, regulation of p53, targeting of the p53-MDM2 interaction for cancer therapy, and
p53-dependent and -independent effects of inhibition of p53-MDM2 interaction. Then, representatives
of small molecule MDM2-p53 binding antagonists are introduced with a focus on those entered into
clinical trials. Furthermore, the review discusses the gene signatures in order to predict sensitivity to
MDM2 antagonists, potential side effects and the reasons for the observed hematotoxicity, mechanisms
of resistance to these drugs, their evaluation as monotherapy or in combination with conventional
chemotherapy or with other targeted therapeutic agents. Finally, it highlights the certainly intriguing
questions and challenges which would be addressed in future studies.
