bims-midomi 2026-09-27 papers

Cell Death Differ. 2026 Sep 23.

DOI: https://doi.org/10.1038/s41418-026-01879-3

Mol Cancer Ther. 2026 Sep 18.

Systematic Evaluation of Combination Strategies with Rezatapopt in p53 Y220C-Mutant Cancer Models.

Tamer Ahmed, Erin E Michaud, Lizhong Xu, Hong Yang, Wenhui Li, Ling Lu, Mary Kate McBrayer, Yvonne Sun, Brandon M Russo, Chris L Mulligan, Josh Battaglia, Melissa L Dumble, Arnold J Levine, Anna M Puzio-Kuter, Masha V Poyurovsky.

Rezatapopt (PC14586), a first-in-class Y220C-selective p53 reactivator, demonstrates single-agent clinical efficacy; however, combinatorial strategies may enhance clinical outcomes. Here, we evaluated rezatapopt in combination with standard-of-care agents (chemotherapy and bevacizumab), murine double minute 2 (MDM2) inhibitors, and a library of FDA-approved compounds. While chemotherapy, bevacizumab, and MDM2 inhibitors showed in vivo efficacy, a high-throughput screen identified the phosphoinositide 3-kinase (PI3K)/ Protein Kinase B (AKT)/mechanistic target of rapamycin (mTOR) and mitogen-activated protein kinase pathways as top synergistic candidates. Validation confirmed that PI3Kα inhibition synergized with rezatapopt to deepen apoptosis and tumor growth inhibition in xenograft models. Thus, PI3K/mTOR pathway inhibition may represent a clinically actionable, conserved p53-reactivation vulnerability across diverse histologies harboring a TP53 Y220C mutation.

DOI: https://doi.org/10.1158/1535-7163.MCT-26-0264

Am J Transl Res. 2026 ;18(8): 7391-7404

Computational screening of natural product inhibitor stargeting the MDM2-p53 interaction: docking and molecular dynamics insights for retinoblastoma therapy.

Yulei Geng, Xiaoli Liu, Sanjay Kumar, Yuxin Geng.

OBJECTIVES: To identify potential natural-product-derived inhibitors of the MDM2-p53 interaction for retinoblastoma therapy through an integrated computational screening strategy and to evaluate their binding stability, pharmacokinetic properties, and electronic characteristics.
METHODS: The crystal structure of MDM2 (PDB ID: 3VZV) was validated using ERRAT and Ramachandran plot analyses. A curated natural compound library from the COCONUT database was screened by molecular docking using PyRx. Top-ranked compounds were evaluated through ADMET and toxicity prediction using SwissADME and Protox 3.0. The selected lead compound, Pentamorphone, was further investigated by 500-ns molecular dynamics simulations, MM/GBSA and MM/PBSA binding free-energy calculations, and density functional theory (DFT) analyses.
RESULTS: Pentamorphone demonstrated favorable binding within the MDM2 hydrophobic pocket and exhibited acceptable pharmacokinetic and toxicity profiles. Molecular dynamics simulations confirmed the stability of the MDM2-Pentamorphone complex, as evidenced by stable RMSD, RMSF, radius of gyration, and persistent hydrogen-bond interactions throughout the 500-ns trajectory. Binding free-energy calculations indicated thermodynamically favorable complex formation, with MM/GBSA and MM/PBSA energies of -60.41 and -58.72 kcal/mol, respectively. DFT analysis revealed a HOMO-LUMO energy gap of 3.96 eV, supporting the compound's electronic stability and potential for favorable target interactions.
CONCLUSIONS: The integrated computational analyses identified Pentamorphone as a promising candidate capable of disrupting the MDM2-p53 interaction. These findings support its further experimental evaluation as a potential therapeutic lead for retinoblastoma characterized by MDM2-mediated suppression of p53.

Keywords: ADMET profiling; MDM2-p53 interaction; MM/GBSA; MM/PBSA; density functional theory (DFT); molecular docking; molecular dynamics simulations; natural product inhibitors; retinoblastoma therapy

DOI: https://doi.org/10.62347/LYUA9855