bims-midomi 2026-05-10 papers

bims-midomi

Biomed News

on MDM2 and mitochondria

Issue of 2026–05–10
seven papers selected by
Gavin McStay, Liverpool John Moores University

MDM2 inhibitors in myeloid cancers: from basic biology to clinical use in myeloproliferative neoplasms.
Clinicopathologic evaluation of dedifferentiated liposarcoma lacking MDM2 amplification.
Discovery of novel MDM2 inhibitors from a Penicillium metabolome library: An integrated phylogenetic, machine learning, and molecular simulation approach.
Inhibiting MDM2 enhances RIPK3-mediated necroptosis and synergizes with immune checkpoint blockade therapy.
Conditional deletion of MDM2 in neurons impairs neuronal homeostasis and cognitive ability.
Design, computational profiling, synthesis and biological evaluation of novel 1,2,4-triazole based derivatives as antioxidant and potent p53-MDM2 inhibitors.
Dexmedetomidine attenuates Alzheimer's pathogenesis by targeting the ROS-mediated XIAP-MDM2-p53 signaling axis.

Leukemia. 2026 May 05.

MDM2 inhibitors in myeloid cancers: from basic biology to clinical use in myeloproliferative neoplasms.

Haifa K Al-Ali, Sarah T Heidel, Francesca Palandri, Florian H Heidel.

Pharmacologic targeting of murine double minute 2 (MDM2) represents one of the most compelling strategies for therapeutic reactivation of wild-type p53 in hematologic malignancies. The MDM2-p53 autoregulatory loop is a central regulator of cellular stress responses, and in myeloid neoplasms-including acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN)-p53 is frequently retained but functionally suppressed through MDM2 overexpression and oncogenic signaling, notably via JAK-STAT activation. Over the past decade, successive generations of MDM2 inhibitors have translated structural and mechanistic insights into clinical investigation, yielding critical lessons regarding dosing paradigms, hematologic toxicity, biomarker-driven patient selection, and mechanisms of resistance, including TP53-mutant clonal selection. While early phase III trials in AML were negative, recent studies in myelofibrosis demonstrate clinically meaningful spleen, symptom, and molecular responses, supporting disease-modifying potential in TP53-wild-type settings. Adaptive platform designs and rational combinations with JAK inhibitors, BCL-2 antagonists, and interferons have further refined therapeutic strategies. Emerging MDM2 degraders and next-generation agents aim to overcome feedback limitations and improve therapeutic index. This review integrates mechanistic foundations, clinical development, resistance biology, and future directions, highlighting how decades of basic science have reshaped p53 reactivation into a precision therapeutic paradigm in myeloid disease.

DOI: https://doi.org/10.1038/s41375-026-02975-6
Histopathology. 2026 May 07.

Clinicopathologic evaluation of dedifferentiated liposarcoma lacking MDM2 amplification.

Charlotte I Wang, Soma Jobbagy, Anne B Giersch, Jonathan B Greer, Kevin X Liu, Gregory M Cote, Yin P Hung, G Petur Nielsen, Ivan Chebib.

   INTRODUCTION: Dedifferentiated liposarcoma (DDLPS) is a typically non-lipogenic malignant neoplasm that arises from progression of an underlying atypical lipomatous tumour/well-differentiated liposarcoma (ALT/WDLPS) and is classically defined by amplification of chromosome 12q15, including MDM2 and frequently cyclin-dependent kinase 4 (CDK4). Detection of MDM2 amplification by fluorescence in situ hybridization (FISH) and/or MDM2 protein expression immunohistochemistry (IHC) has, therefore, become central to the diagnosis of DDLPS, particularly in small biopsies from the retroperitoneum. Rare exceptions to this paradigm have been described, but the clinicopathologic and molecular spectrum of MDM2 non-amplified DDLPS remains poorly characterized. We report a series of MDM2 non-amplified DDLPS to better define their diagnostic features, genomic alterations and clinical behaviour.
METHODS: Pathology archives from 2010 to 2025 were queried for cases diagnosed as DDLPS. Inclusion criteria required a high-grade sarcoma arising in a histologically confirmed ALT/WDLPS background, absence of MDM2 overexpression by IHC and lack of MDM2 amplification by FISH and/or single nucleotide polymorphism array. Clinicopathologic features, immunophenotype, treatment and outcomes were reviewed.
RESULTS: Among 253 cases of DDLPS identified during the study period, four (1.6%) fulfilled criteria for MDM2-negative DDLPS. All tumours arose in the retroperitoneum or intra-abdominal soft tissues and demonstrated high-grade sarcoma morphology with an associated WDLPS component on resection. Despite the absence of MDM2 amplification, all cases showed strong CDK4 expression by IHC. Molecular analysis revealed recurrent alterations involving cell-cycle regulation, including CDK4 copy number gain in all cases and loss of CDKN2A in three. Two cases harboured TP53 alterations. Clinically, outcomes were heterogeneous, ranging from aggressive disease with rapid recurrence and death within months to prolonged disease-free survival exceeding 5 years.
CONCLUSION: MDM2 non-amplified DDLPS represents a rare subset of DDLPS that appear to be driven by alternative mechanisms of cell-cycle dysregulation, most commonly involving CDK4 gain and CDKN2A loss, with occasional TP53 alterations. Awareness of this variant is critical to avoid misclassification as other high-grade sarcomas, particularly on limited biopsies, and underscores the importance of integrating morphology, IHC and broad genomic profiling in diagnostically challenging retroperitoneal sarcomas.

Keywords:  CDK4; CDKN2A; MDM2; dedifferentiated; liposarcoma; sarcoma

DOI:  https://doi.org/10.1111/his.70174
J Mol Graph Model. 2026 Apr 30. pii: S1093-3263(26)00152-X. [Epub ahead of print]146 109426

Discovery of novel MDM2 inhibitors from a Penicillium metabolome library: An integrated phylogenetic, machine learning, and molecular simulation approach.

Prince Danan Biniyam, Naomi Kayeri, Jesse Ayim Buabeng, Dickson Aboagye, Alberta Hammah, Syed Arslan Haider, Lawrence Kwame Nkrumah, Kwabena Adu-Adjei, Victoria Ohene-Adu, Michael Osei, Clifford Tignangnen Penajah, Peter Bedman Narh, Cedric Dzidzor Kodjo Amengor.

  Restoring the tumor-suppressor function of p53 by inhibiting its negative regulator, MDM2, represents a significant therapeutic avenue for cancers that maintain wild-type p53. This research aimed to identify new MDM2 inhibitors through a phylogenetically guided strategy that involved the construction of a focused virtual library of metabolites derived from the Penicillium genus. A comprehensive computational framework was developed, employing machine learning-based quantitative structure-activity relationship (ML-QSAR) modeling, ensemble molecular docking, network pharmacology, molecular dynamics (MD) simulations, and ADMET profiling. The gradient boosting ML-QSAR model achieved a test set R2 of 0.80 and was externally validated against 39 known MDM2 inhibitors (R2 = 0.82, RMSE = 0.80 pIC50 units), confirming its predictive reliability. Ensemble docking studies against 13 conformations of MDM2 highlighted three leading candidates (CNP0147553.1, CNP0154476.3, and CNP0154476.4) demonstrating binding affinities comparable to the known control inhibitor Nutlin-3a, with docking scores validated against experimental binding data. Further investigations through 500 ns MD simulations provided insights into the stability of the CNP0147553.1-MDM2 complex, which maintained a mean ligand RMSD of 0.039 nm and a complex RMSD of 0.176 nm, alongside a favorable binding free energy of -25.82 kcal/mol. Key residue analysis revealed that CNP0147553.1 achieved pronounced stabilization of critical binding pocket residues, including an 81.6% reduction in flexibility of HIS96. Network pharmacology analysis revealed a polypharmacology potential, indicating that the hub genes related to the identified compounds predominantly converged on the PI3K-AKT-mTOR and RAS-RAF-MAPK signaling pathways. ADMET profiling suggested promising pharmacokinetic and safety profiles for the lead candidates, establishing the basis for future experimental validation.

Keywords:  Ensemble docking; MDM2 inhibitors; Machine learning QSAR; Molecular dynamics simulations; Natural product drug discovery; Network pharmacology; Penicillium metabolites; p53 tumor suppressor

DOI:  https://doi.org/10.1016/j.jmgm.2026.109426
iScience. 2026 May 15. 29(5): 115724

Inhibiting MDM2 enhances RIPK3-mediated necroptosis and synergizes with immune checkpoint blockade therapy.

Yingxin Wu, Hanyang Yu, Zongxu Zhang, Weihang Xiong, Zexian Zeng, Weili Liu, Hailin Tu, Xin Lin.

  Necroptosis is a form of programmed cell death that promotes tumor immunogenicity. To identify druggable regulators of necroptosis, we performed a small-molecule inhibitor screen and identified mouse double minute 2 (MDM2) as a suppressor of tumor necrosis factor α (TNF-α)-induced necroptosis. Genetic deletion or pharmacologic inhibition of MDM2 markedly enhanced necroptosis in a receptor-interacting protein kinase 1 (RIPK1)-dependent and p53-independent manner. Mechanistically, MDM2 interacted with RIPK3 and promoted its proteasome-mediated degradation, thereby limiting RIPK3 abundance and restraining pathway activation. In vivo, MDM2 deficiency increased tumor cell necroptosis, promoted inflammatory remodeling of the tumor microenvironment (TME), and enhanced CD8+ T cell infiltration, leading to improved tumor control. In immunologically "cold" tumor models, combining MDM2 inhibition with anti-PD-1 blockade converted tumors to a T cell-inflamed state and significantly improved therapeutic efficacy, even in p53-deficient settings. These findings identify MDM2 as a regulator of TNF-α-induced necroptosis and highlight its potential as a therapeutic target for cancer immunotherapy.

Keywords:  cancer; cell biology; immune response

DOI:  https://doi.org/10.1016/j.isci.2026.115724
J Adv Res. 2026 May 02. pii: S2090-1232(26)00377-2. [Epub ahead of print]

Conditional deletion of MDM2 in neurons impairs neuronal homeostasis and cognitive ability.

Ying Jin, Hengzhen Cui, Junya Kang, Wenqi Chen, Chuanlin Zhang, Chun Zhang, Yunyun Han, Xianfang Meng.

   INTRODUCTION: Murine double minute 2 (MDM2) has been implicated in diverse neurological disorders, yet its precise function in the central nervous system remains poorly defined.
OBJECTIVES: This study aimed to elucidate the roles of MDM2 in postnatal forebrain development, synaptic function, and cognition by generating and analyzing a forebrain-specific conditional knockout (cKO) model.
METHODS: We generated a forebrain-specific conditional knockout mouse line in which MDM2 was selectively ablated under the control of the CaMKIIα promoter. We employed morphometric analysis, Western blot, whole-cell patch-clamp recordings in hippocampal pyramidal neurons, in vivo two-photon calcium imaging in the primary visual cortex, and behavioral tests (Y-maze, novel object recognition, Morris water maze) to assess memory and learning.
RESULTS: MDM2 cKO mice exhibited severe microcephaly, characterized by cortical thinning, hippocampal shrinkage, and reduced neuronal density alongside glial proliferation. Synaptic deficits were evident from reduced synaptic protein levels, dendritic spine loss, and impaired long-term potentiation. Moreover, MDM2-deficient neurons showed intrinsic hyperexcitability. In vivo calcium imaging revealed normal mean response to visual stimulus but impaired cortical computation, with reduced population coding capacity for naturalistic stimuli. Behaviorally, MDM2 cKO mice displayed profound deficits in spatial memory, object recognition, and spatial learning.
CONCLUSIONS: Our findings establish MDM2 as a critical regulator of postnatal cortical structure, synaptic plasticity, and cognitive function, highlighting its potential as a therapeutic target for neurodevelopmental disorders with cognitive deficits.

Keywords:  Cognitive deficits; MDM2; Neuronal homeostasis; Synaptic plasticity

DOI:  https://doi.org/10.1016/j.jare.2026.05.003
Bioorg Chem. 2026 May 05. pii: S0045-2068(26)00484-0. [Epub ahead of print]178 109948

Design, computational profiling, synthesis and biological evaluation of novel 1,2,4-triazole based derivatives as antioxidant and potent p53-MDM2 inhibitors.

Dushyant D Kotadiya, Pooja S Thakur, Ruchi Nair, Apurva Prajapati, Dharmesh A Patel, Siddharth S Patel, Shilpa Kumari, Kanu Priya, Hitesh D Patel.

  Cancer remains the second leading cause of death globally, primarily because of the shortcomings of existing treatments, which include early drug resistance, metastasis, inadequate pharmacokinetics, and systemic toxicity. Small-molecule inhibitors that target the interaction of MDM2 and p53 show promise for reactivating p53 function and suppressing tumor growth. In this study, we designed, produced, and evaluated a number of 2-(4-((2,4-difluorobenzylidene)amino)-5-mercapto-4H-1,2,4-triazol-3-yl)phenol derivatives as possible anticancer agents utilizing both in silico and in vitro approaches. All obtained compounds showed effective binding interactions, as evidenced by their high docking scores. Molecular dynamics (MD) simulations validated the structural stability, compactness, and rigidity of the most active molecule during a 100 ns time period. ADMET predictions indicated good pharmacokinetic parameters and low toxicity profiles, whereas DFT investigates validated the compounds' reactive features and electronic compatibility for biological activity. The structures of the synthesized compounds were confirmed through 1H NMR, 13C NMR, IR, and ESI-MS analyses. The anticancer activity in vitro was assessed using the MTT assay on MCF-7 and A549 cell lines. Of all the compounds tested, compound 8D, N-(benzo[d]thiazol-2-yl)-2-((4-((2,4-difluorobenzylidene)amino)-5-(2-hydroxyphenyl)-4H-1,2,4-triazol-3-yl)thio)acetamide, exhibited the strongest activity against MCF7 & A549 cells, with an IC₅₀ value of 7.56 & 7.22 μM respectively. This study identifies a new class of small-molecule inhibitors that interact with p53 and MDM2, characterized by low toxicity and high efficacy, which could be turned into anticancer drugs. These findings are essential for medicinal chemists and researchers working on the discovery of anticancer medicines.

Keywords:  1,2,4-triazole-3-thiol; Anticancer activity; In-vitro study; MD simulation; Molecular docking; p53-MDM2 inhibitors

DOI:  https://doi.org/10.1016/j.bioorg.2026.109948
Front Pharmacol. 2026 ;17 1811373

Dexmedetomidine attenuates Alzheimer's pathogenesis by targeting the ROS-mediated XIAP-MDM2-p53 signaling axis.

Weiwei Wu, Hui Wang, Luyao Zhang, Danqing Li, Yuxiang Chen, Bolin Lin, Huiqin Jiang, Ting Meng, Zheao Zhu, Lijun He, Hui Zhang, Hu Liu, Ruijie Zhang.

   Introduction: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with a complex pathological process, in which oxidative stress serves as a key pathogenic mechanism. Studies have shown that the anesthetic adjuvant dexmedetomidine (Dex) can improve postoperative cognitive function in AD patients. This study aimed to explore whether dexmedetomidine alleviates AD-associated neuronal apoptosis and cognitive impairment via reducing overproduction of ROS and regulating the XIAP signaling pathway.
Methods: In vitro experiments were conducted using Aβ1-42-exposed SH-SY5Y cells and primary neurons, employing interventions such as the ROS scavenger NAC, yohimbine pre-treatment, and siRNA-mediated XIAP knockdown. In vivo cognitive deficits and brain pathology were evaluated in AD model mice using Morris water maze tests and immunofluorescence staining.
Results: Experimental results demonstrated that Aβ1-42 induced apoptosis in neuronal cells, while dexmedetomidine incubation significantly reduced Aβ1-42 elicited ROS generation, activated XIAP, suppressed MDM2 and ameliorated P53 overactivation, thereby effectively preventing neuronal death. Combined administration of NAC and dexmedetomidine reversed Aβ1-42-induced XIAP inhibition, ROS accumulation, and cell apoptosis. Furthermore, both yohimbine pre-treatment and XIAP knockdown effectively abrogated the ability of Dex to reduce ROS accumulation and mitigate apoptosis. In vivo results indicated that dexmedetomidine improved cognitive deficits and intervened in AD pathology in the hippocampal region of AD model mice.
Conclusion: This study reveals that dexmedetomidine inhibits ROS release and activates the XIAP-MDM2-p53 signaling pathway, thereby delaying apoptosis and ameliorating cognitive impairment in AD progression.

Keywords:  dexmedetomidine; morris water maze; mouse double minute 2 homolog; poly-D-lysine; tumor protein p53

DOI:  https://doi.org/10.3389/fphar.2026.1811373