AUTHOR=Attili Marika , Valentini Sonia , Pesavento Maria , Ballarotto Marco , Scognamiglio Viviana , Pontecorvi Alfredo , Macchiarulo Antonio , Saccoccia Fulvio , Moretti Fabiola 

TITLE=Exploring the heterodimer MDM2/MDM4 interaction region uncovers high-affinity peptides for therapeutic p53-reactivation

JOURNAL=Frontiers in Chemical Biology

VOLUME=Volume 4 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/chemical-biology/articles/10.3389/fchbi.2025.1576640

DOI=10.3389/fchbi.2025.1576640

ISSN=2813-530X

ABSTRACT=IntroductionIn the era of targeted therapies, molecules for the reactivation of the oncosuppressor p53 in human cancer have not yet reached FDA or EMA approval. Recently, the interaction region of the MDM2/MDM4 heterodimer, the most efficient inhibitor of p53 levels and function, has been successfully targeted. Disruption of the heterodimer activated p53 oncosuppressive function in vitro and in vivo. Despite these encouraging results, further studies on the MDM2/MDM4 interaction region have yet to progress.MethodsHere, we undertook a detailed bioinformatic and biochemical analysis of this region. Using molecular dynamics simulation followed by umbrella sampling.Results and discussionWe characterized a short peptide and modified derivatives with increased binding affinity and pharmacodynamics features compared to previous molecules. Our results uncover the intrinsic plasticity of the MDM2 RING domain through different binding clefts and provide evidence of its ability to host different peptides by key residues. This data may guide the development of next-generation therapeutic inhibitors.