Abstract B028: Unravelling the molecular structural and functional roles of the homologous mouse double minute RINGs interface for targeted anticancer design

Abstract The new yearly 1.1 million cancer surge cases and considerably increasing mortality, after two decades of decline, require urgent and effective therapy. Targeted anticancer therapy is an attractive strategy against cancer using critical receptors. Homologous Mouse Double-Minute RINGs (MDM2-MDMX) negatively regulate the p53 tumour-suppressing role by inhibiting its transcriptional activity and promoting proteasomal degradation in tumour types. Interventively, Hinokiflavone/Hinok, MMRi62, MMRi64, and MMRi71 exert a therapeutic downregulation against MDM2-MDMX by activating p53’s apoptotic arm, a mechanism that is still unclear. This study reveals the underlying dynamic conformational stabilities of the MDM2G443T-MDMX interface and its mechanistic inhibition. Integrated software visualisations/computations of the all-atoms MD simulated systems revealed relative stability (lower_RMSD_values), flexibility (higher_RMSF_values), and highly inter-residual displacement among unbound and inhibitor-bound systems. The ligand-bound MDM2G443T-MDMX showed remarkable secondary structure transitions. MMGB(PB)SA binding free energies (-22.69, -26.42, -20.30 kcal/mol) revealed promising inhibitors’-MDM2G443T-MDMX interactions. ARG13, PRO45, LYS42, and PRO14 have the highest binding energy contributions to the RINGs. Hinok showed dual interactions with MDM2G443T-MDMX RINGs over 200 ns, indicating dual potential inhibition compared to the interactions of the MMRis with MDM2 only. These findings provide deep molecular insights into the MDM2G443T-MDMX RINGs conformation and can be extrapolated to inhibitors' downregulatory induction for future potential anticancer development. Citation Format: Adeniyi Thompson. Adewumi, Salerwe Mosebi. Unravelling the molecular structural and functional roles of the homologous mouse double minute RINGs interface for targeted anticancer design [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr B028.