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Targeting the MDM2-p53 Interaction for Cancer Therapy

Authors' Affiliations: ¹ Comprehensive Cancer Center and Departments of ² Internal Medicine, ³ Pharmacology, and ⁴ Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan

Requests for reprints: Shaomeng Wang, The University of Michigan, CCGC/3215, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0934. Phone: 734-615-0362; Fax: 734-647-9647; E-mail: shaomeng{at}umich.edu.

Abstract

p53 is a powerful tumor suppressor and is an attractive cancer therapeutic target because it can be functionally activated to eradicate tumors. The gene encoding p53 protein is mutated or deleted in half of human cancers, which inactivates its tumor suppressor activity. In the remaining cancers with wild-type p53 status, its function is effectively inhibited through direct interaction with the human murine double minute 2 (MDM2) oncoprotein. Blocking the MDM2-p53 interaction to reactivate the p53 function is a promising cancer therapeutic strategy. This review will highlight the advances in the design and development of small-molecule inhibitors of the MDM2-p53 interaction as a cancer therapeutic approach.