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.