Targeting the MDM2/MDM4 Interaction Interface as a Promising Approach for p53 Reactivation Therapy

Abstract

Restoration of wild-type p53 tumor suppressor function has emerged as an attractive anticancer strategy. Therapeutics targeting the two p53-negative regulators, MDM2 and MDM4, have been developed, but most agents selectively target the ability of only one of these molecules to interact with p53, leaving the other free to operate. Therefore, we developed a method that targets the activity of MDM2 and MDM4 simultaneously based on recent studies indicating that formation of MDM2/MDM4 heterodimer complexes are required for efficient inactivation of p53 function. Using computational and mutagenesis analyses of the heterodimer binding interface, we identified a peptide that mimics the MDM4 C-terminus, competes with endogenous MDM4 for MDM2 binding, and activates p53 function. This peptide induces p53-dependent apoptosis in vitro and reduces tumor growth in vivo. Interestingly, interfering with the MDM2/ MDM4 heterodimer specifically activates a p53-dependent oxidative stress response. Consistently, distinct subcellular pools of MDM2/MDM4 complexes were differentially sensitive to the peptide; nuclear MDM2/MDM4 complexes were particularly highly susceptible to the peptide-displacement activity. Taken together, these data identify the MDM2/MDM4 interaction interface as a valuable molecular target for therapeutic reactivation of p53 oncosuppressive function.

The Double Role of p53 in Cancer and Autoimmunity and Its Potential as Therapeutic Target

“…Therefore, recent studies attempted to develop dual MDM2/MDM4 inhibitors [44,59]. At last, the possibility to reactivate p53 in tumors by the use of a peptide that targets the MDM2/MDM4 heterodimer was exploited [60]. This approach allows the inhibition on p53 to be released more effectively.…”

“…Discovery of new molecular targets for treatment of pathological conditions at increased incidence worldwide is an area in which considerable efforts are being employed to develop new and safe therapeutic agents [60]. In the light of the aforementioned acquired knowledge and discussion on the functional properties of p53 and its regulatory pathways, this protein can offer a focused target for future therapeutic perspectives in oncology and chronic inflammatory disorders that lead to autoimmunity.…”

“…Recently, in addition to reactivating p53 by targeting the interface between the protein and MDM2 or MDM4, novel strategies have been proposed that interfere with MDM2/MDM4 heterodimerization [60] (Figure 2). These can also open up new pathways for treatment of autoimmunity and associated conditions of cancer and autoimmune diseases.…”

MDM2 oligomers: antagonizers of the guardian of the genome

“…In an even more recent study using computational and rational methods, a peptide-based inhibitor of MDM2–MDMX oligomerization was reported. 126 This inhibitor, named Peptide3, showed a p53-dependent apoptotic response; however, its reported mechanism of action is peculiar in that only nuclear MDM2–MDMX heterooligomerization is affected. Perhaps using a more thorough and unbiased screening method, such as phage display, coupled with emerging peptide technologies, such as peptide stapling, could yield even more effective peptide-based MDM2–MDMX oligomerization inhibitors.…”

MDM2–MDM4 molecular interaction investigated by atomic force spectroscopy and surface plasmon resonance

“…[12][13][14][15][16][17][18] Therefore, the interaction between MDM2 and MDM4 could be an appropriate target to design a highly effective cancer therapy. [19][20][21] Indeed, designing specific antagonists for the heterodimeric complex could prevent the formation of the MDM2-MDM4 complex and thus abolish its inhibitory activity, with restoration of the p53 oncosuppressive function.…”