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190 Novel Classes of p53 Activators for Cancer Therapy

Lu, Wuyuan; Pazgier, Marzena; Liu, Min; Li, Chong; Li, Changqing; Mao, Yubin; Yuan, Weirong

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 2011 - Volume 56 - Issue - p 80
doi: 10.1097/01.qai.0000397372.08696.00

Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD

The activity and stability of the tumor suppressor protein p53 is negatively regulated in many cancers including virally induced, ADIS-defining Kaposi's sarcoma and pleural effusion lymphoma. One of the major negative regulators of p53 is an E3 ubiquitin ligase known as MDM2, which binds p53 to block p53-mediated growth inhibitory and apoptotic responses to cellular stress and to target the tumor suppressor protein for proteasomal degradation. Amplification and/or over-expression of MDM2 confer p53 inactivation and tumor development; inhibitors of the p53-MDM2 interaction can activate the p53 pathway and inhibit tumor growth in vitro and in vivo. Thus, antagonizing MDM2 to activate p53 represents a new therapeutic paradigm for cancer treatment. Using a battery of biochemical, biophysical and structural tools in combination with phage-expressed peptide library screening and structure-based rational design, we have recently identified three different classes of potent p53 activators based on L-peptides, miniature proteins, and D-peptides.

In this presentation we describe the discovery of these novel MDM2 antagonists, their structural as well as functional properties, and their application as potential antitumor agents to cancer therapy.

Copyright © 2011 Wolters Kluwer Health, Inc. All rights reserved.