bims-midomi Biomed News
on MDM2 and mitochondria
Issue of 2025–05–11
two papers selected by
Gavin McStay, Liverpool John Moores University
  1. Anti-cancer activity elucidation of geissolosimine as an MDM2-p53 interaction inhibitor: An in-silico study.
  2. Synergistic Activity of Combined FLT3-ITD and MDM2 Inhibition With Quizartinib and Milademetan in FLT3-ITD Mutant/TP53 Wild Type Acute Myeloid Leukemias.
  1. PLoS One. 2025 ;20(5): e0323003
    Anti-cancer activity elucidation of geissolosimine as an MDM2-p53 interaction inhibitor: An in-silico study.
    Md Al-Amin, Rehnuma Tanjin, Md Rasul Karim, Jannatul Mawa Etee, Ayesha Siddika, Nafisa Akter, Md Helal Uddin, Ratul Mahmud, Tasfia Saffat, Md Faruk Hossen, Samira Idris Mowlee, Elmu Kabir Rafa, Sumi Akter.
      For cancer treatment, Inhibition of murine double minute (MDM2) & p53 interaction is considered an attractive therapeutic approach. In this study, we performed an integrated virtual screening (i.e., QSAR, structural similarity, molecular docking, and molecular dynamic simulation) on the in-house building alkaloids library. Geissolosimine (i.e., an indole alkaloid) was predicted as a potential inhibitor for MDM2-p53 interaction. The predicted pIC50 value of Geissolosimine, was 7.013 M. Moreover, Geissolosimine showed 0.62% structural similarity to 'SAR405838' (i.e., a clinical trial inhibitor for MDM2-p53 interaction inhibition); and a docking score of -10.9 kcal/mol that was higher than the 'SAR405838'.100 ns molecular dynamics simulation (MDS) was performed to validate the docking result and it exhibited better binding stability to MDM2. The pharmacokinetic & drug-likeness analysis suggested that Geissolosimine had potential to be a drug-like compound. However, in vitro & in vivo assays will be required to validate this study.
    DOI:  https://doi.org/10.1371/journal.pone.0323003
  2. Clin Cancer Res. 2025 May 06.
    Synergistic Activity of Combined FLT3-ITD and MDM2 Inhibition With Quizartinib and Milademetan in FLT3-ITD Mutant/TP53 Wild Type Acute Myeloid Leukemias.
    Weiguo Zhang, Li Li, Muharrem Muftuoglu, Mahesh Basyal, Noriko Togashi, Koichi Iwanaga, Fumie Tanzawa, Masashi Numata, Dale L Bixby, Harry P Erba, Nikolai Podoltsev, Gary J Schiller, Prasanna Kumar, Arnaud Lesegretain, Takeshi Isoyama, Takahiko Seki, Naval Daver, Michael Andreeff.
       PURPOSE: Acute myeloid leukemia (AML) is characterized by frequent mutation of fms-like tyrosine kinase 3 (FLT3), overexpression of murine double minute 2 (MDM2), and TP53 wild type (WT). Monotherapies targeting FLT3 frequently result in the development of resistant disease. Here, we investigated the antileukemia efficacy of co-targeting FLT3 and MDM2 with quizartinib and milademetan (Q/M) in FLT3-internal tandem duplication (ITD) AML cell lines, xenograft and patient-derived xenograft (PDX) models, and a phase 1 clinical trial.
    METHODS: Preclinical studies used human and murine cell lines carrying FLT3-ITD, and/or TKD mutations and TP53 WT/knockdown, leukemia cell xenograft models and a PDX model. Assays were conducted using milademetan (DS-3032b) and murine-specific MDM2i (DS-5272). An open-label, phase 1, dose-escalation clinical trial (ClinicalTrials.gov NCT03552029) was conducted.
    RESULTS: Dual inhibition of FLT3-ITD and MDM2 synergistically induced apoptosis in FLT3-ITD/TP53 WT AML and venetoclax-resistant cell lines, reduced tumor burden, and improved survival in xenograft and PDX models of FLT3-ITD AML. Phase 1 clinical data indicated favorable safety and tolerability for the Q/M combination treatment. Complete responses with incomplete hematologic recovery were achieved in 40% of relapsed/refractory AML patients. Unsupervised single-cell proteomics analysis showed Q/M treatment decreased the expression of prosurvival (pERK, pAKT, Mcl-1) proteins and activated protein signaling downstream of p53 including PUMA. YTHDF2 was increased post therapy in resistant cells. Q/M combination demonstrated higher activity in CD34+ versus CD34- leukemia blasts.
    CONCLUSIONS: Preclinical and mechanistic rationale and preliminary clinical data support the future development of MDM2/FLT3 targeting strategies for FLT3-mutant AML.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-2764
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