Therapeutic considerations for Mdm2: not just a one trick pony

Abstract

Background: The mdm2 proto-oncogene is elevated in numerous late stage cancers. The Mdm2 protein manifests its oncogenic properties in part through inactivation of the tumor suppressor protein p53. Recent efforts in anticancer drug design have focused on the identification of small molecules that disrupt the Mdm2–p53 interaction, in hope of re-engaging the p53 pathway. Objective: In addition to binding p53, Mdm2 complexes with numerous proteins involved in DNA repair, translation, metabolic activities, tumor growth and apoptosis. Further biochemical analysis is required to understand how Mdm2 integrates into all of these cellular processes. Post-translational modifications to Mdm2 can alter its ability to associate with numerous proteins. Changes in protein structure may also affect the ability of small molecule inhibitors to effectively antagonize Mdm2. Conclusion: The complexity of Mdm2 modification has been largely neglected during the development of previous Mdm2 inhibitors. Future high-throughput or in silico screening efforts will need to recognize the importance of post-translational modifications to Mdm2. Furthermore, the identification of molecules that target other domains in Mdm2 may provide a tool to prevent other pivotal p53-independent functions of Mdm2. These aims provide a useful roadmap for the discovery of new Mdm2-binding compounds with therapeutic potency that may exceed its predecessors.

Keywords::

• DNA-dependent protein kinase
• Hdm2
• Mdmx
• Mdm2
• nutlin compounds
• p53
• RING domain
• small molecule inhibitors

Acknowledgements

Due to page limitation, we apologize for omission of many papers and reviews on other proteins and compounds that interact with MDM2 and post-translational modifications that can occur to the protein.