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 anti-cancer drug design have focused on the identification of small molecules that disrupt the Mdm2-p53 interaction, in hopes 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. Additional 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.

Induction of Apoptotic Genes by a p73-Phosphatase and Tensin Homolog (p73-PTEN) Protein Complex in Response to Genotoxic Stress

“…Therefore, a fine-tuning mechanism between PTEN, p53, p73, and Mdm2 is in place in human cells to mediate cellular apoptosis in response to DNA damage. To this end, Mdm2 represents a viable target for drug design and chemotherapeutic intervention (51)(52)(53).…”

Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery

“…2,8,9 The restoration of the impaired function of a single gene, p53, by directly disrupting the MDM2-p53/MDMX-p53 interactions, offers an attractive new avenue for anticancer therapy across a broad spectrum of cancers. [10][11][12][13][14][15][16][17][18][19][20] Cancer cells have been shown to be extremely sensitive to restoration of p53 function, verifying the expectation of highly effective therapies from this approach [21][22][23][24] and thus an intensive anticancer drug discovery effort is ongoing to develop antagonists of this interaction. While many MDM2 antagonists have been described in patent and scientific literature, no small molecule is known to tightly bind to MDMX.…”

High affinity interaction of the p53 peptide-analogue with human Mdm2 and Mdmx

“…[1][2][3][4][5][6][7][8][9] The rescue of the impaired p53 function by disrupting the Mdm2-p53 interaction offers new strategies for anticancer therapeutics. 2,[9][10][11][12][13][14][15][16][17][18][19][20][21][22] Mdm2 promotes ubiquitination of p53 followed by degradation in proteasome. [1][2][3][4][5][6][7][8][9]23 Although Mdm2 remains the only known essential regulator of p53 stability, recently its homolog, Mdmx, has also emerged as an important player in the regulation of p53 activity.…”

“…[1][2][3][4][5][6][7][8][9]23 Although Mdm2 remains the only known essential regulator of p53 stability, recently its homolog, Mdmx, has also emerged as an important player in the regulation of p53 activity. [1][2][3][4][5]7,15,22,23 It was shown that the high-affinity Mdm2 inhibitors developed so far, e.g., Nutlins [11][12][13][14][15][16][17][18][19][20][21][22][23][24] or Mi219 (reviewed in refs. 11, 14, 15 and 25) are only weakly binding to Mdmx (reviewed in refs.…”