bims-midomi 2026-05-31 papers

bims-midomi

Biomed News

on MDM2 and mitochondria

Issue of 2026–05–31
ten papers selected by
Gavin McStay, Liverpool John Moores University

Navigating the p53-MDM2 Landscape: Molecular Insights and Therapeutic Strategies.
SREBP2-activated CNPY3 Phase Separation Promotes Colorectal Cancer by Enhancing MDM2-mediated p53 Degradation.
Intimal sarcoma, review and future perspectives.
Dispiroindolinone-Glutarimide Conjugates: Synthesis and Evaluation as Potential Hetero-PROTACs for p53 Reactivation.
Antineoplastic multi-targeted spiro[indoline-3,2'-pyrrolidines] incorporating urea function: Rational design, synthesis and bio-properties studies.
Integrated multi-stage screening assisted discovery and optimization of spirooxindole MDM2 inhibitors.
MST4 plays dual roles in lung adenocarcinoma by regulating homeostasis of wild-type and mutant p53 protein.
Liver-specific SIRT1 knockout-induced hyperglycemia promotes spontaneous lung adenocarcinomas through HSF1-MDM2.
Molecular mechanisms underlying liposarcoma subtype transition and proteasome-associated targeted interventions.
A first-in-pediatric study of ALRN-6924, a novel stapled-peptide dual MDM2/MDMX inhibitor, for children with advanced hematologic and solid malignancies.

Arch Pharm (Weinheim). 2026 May;359(5): e70264

Navigating the p53-MDM2 Landscape: Molecular Insights and Therapeutic Strategies.

Mai A Mansour, Ghaneya S Hassan, Khaled A M Abouzid.

  MDM2 is categorised as a critical oncogenic regulator that negatively controls the tumour suppressor p53, making it an important target for cancer therapy. With the aim of restoring the p53 activity through disrupting MDM2-p53 interaction, several strategies, including small-molecule inhibitors, have been developed, thereby promoting cancer cell apoptosis. Numerous chemical scaffolds were widely employed in designing and synthesising MDM2 inhibitors. This review summarises the advances in structure-based drug design and virtual screening approaches that allowed the generation of potent inhibitors with improved binding affinity, selectivity and pharmacokinetic profiles. We also discuss limitations such as chemical stability and innovative approaches such as targeted MDM2 degradation.

Keywords:  MDM2 inhibitors; PROTAC; apoptosis; p53‐MDM2 interaction; wild‐type p53

DOI:  https://doi.org/10.1002/ardp.70264
Int J Biol Sci. 2026 ;22(10): 5301-5319

SREBP2-activated CNPY3 Phase Separation Promotes Colorectal Cancer by Enhancing MDM2-mediated p53 Degradation.

Xue Li, Min-Yue Yin, Yan-Fei Wei, Jie Xing, Qian Zhang, Ye Zong, Shu-Tian Zhang, Si-An Xie.

  Dysregulated cholesterol metabolism is a recognized metabolic hallmark of cancer. While the transcription factor SREBP2 is a master regulator of this pathway, how its activation converts metabolic stress into the development of carcinogenic signals in colorectal cancer (CRC) remains unclear. Through clinical and preclinical analyses, we first confirmed that hypercholesterolemia and elevated tumoral SREBP2 are hallmarks of CRC. Using multi-omics integration, we identified CNPY3 as a direct transcriptional target of SREBP2. Functionally, CNPY3 drives CRC cell proliferation, invasion, and tumor growth via a cholesterol synthesis-independent oncogenic program. Clinically, high CNPY3 expression robustly correlated with advanced disease and poor patient survival. Mechanistically, we discovered that CNPY3 undergoes liquid-liquid phase separation (LLPS), a property dependent on its intrinsically disordered C-terminal region. This LLPS capacity is essential for its oncogenic function, as it enables CNPY3 to enhance MDM2 phosphorylation at the activating Ser166 site and promote its nuclear translocation. Consequently, CNPY3 potentiates MDM2-mediated ubiquitination and degradation of the tumor suppressor p53. Genetic ablation of p53 completely abolished the pro-tumorigenic effects of CNPY3, confirming p53 as the critical downstream effector. Crucially, this axis specifically targets wild-type p53, having no effect on common p53 mutants. Pharmacological disruption of the MDM2-p53 interaction with Nutlin-3 effectively reversed CNPY3-driven malignancy both in vitro and in vivo. Our work unveils a SREBP2-CNPY3-MDM2-p53 signaling axis that links cholesterol metabolic dysregulation to p53 pathway inactivation in CRC. We further established that the oncogenic activity of CNPY3 is mediated through its biophysical property of LLPS. These findings nominate CNPY3 as a novel prognostic biomarker and a compelling therapeutic target for p53-wild-type CRC.

Keywords:  CNPY3; Cholesterol Metabolism; Colorectal Cancer; Liquid-liquid phase seperation; MDM2; SREBP2

DOI:  https://doi.org/10.7150/ijbs.125792
Curr Opin Oncol. 2026 May 20.

Intimal sarcoma, review and future perspectives.

Santiago López Subires, Naroa Amondarain Amenabar, Claudia Valverde.

   PURPOSE OF REVIEW: Intimal sarcoma is an exceptionally rare and aggressive vascular malignancy that remains frequently misdiagnosed. This review synthesizes recent advances in epidemiology, diagnosis, molecular characterization and treatment, highlighting why updated guidance is urgently needed.
RECENT FINDINGS: Current literature emphasizes persistent diagnostic delays due to nonspecific clinical and radiological features. Molecular studies consistently show recurrent amplification of MDM2, PDGFRA and CDK4 as key oncogenic drivers. Surgical resection remains the only potentially curative option, although complete removal is often challenging. Retrospective data suggest that multimodal therapy, particularly anthracycline-based chemotherapy, may improve outcomes in selected patients. Targeted therapies and immunotherapy have shown limited but emerging activity in moleculary defined subgroups.
SUMMARY: Despite incremental progress, prognosis remains poor, underscoring the need for earlier recognition, molecularly guided treatment strategies and clinical trial participation. Management in specialized multidisciplinary centers is essential to optimized care and advance research in this ultra-rare sarcoma.

Keywords:  MDM2 amplification; intimal sarcoma; vascular sarcoma

DOI:  https://doi.org/10.1097/CCO.0000000000001246
Molecules. 2026 May 10. pii: 1602. [Epub ahead of print]31(10):

Dispiroindolinone-Glutarimide Conjugates: Synthesis and Evaluation as Potential Hetero-PROTACs for p53 Reactivation.

Vladislav S Polyakov, Yuri K Grishin, Viktor A Tafeenko, Ekaterina S Ivanova, Sofya S Pogodaeva, Daniil V Moldavskii, Alexander A Shtil, Elena K Beloglazkina.

  A convergent scheme for the preparation of conjugates with the dispiroindolinone-pyrrolidine-thioimidazolone and glutarimide moieties connected via a triazole-containing linker is proposed. Target conjugates were synthesized by azide-alkyne (3+2) cycloaddition reactions between propargylthio-substituted dispiroindolinone-pyrrolidine-imidazolones and an azido-glutarimide derivative. The starting compounds were available isothiocyanates, glycine, substituted benzaldehydes, chloroacetamide, and ethyl acrylate. The key azide-alkyne (3+2) cycloaddition step was carried out using TBTA as a catalyst, achieving >70% product yields. The resulting bifunctional compounds contained a fragment of dispiroindolinone (a p53-MDM2 interaction inhibitor) and glutarimide, a ubiquitin ligase ligand. The obtained dispiroindolinone-glutarimide conjugates were tested for their potential as hetero-PROTAC compounds for p53 reactivation. Individual conjugates showed preferential cytotoxicity against HCT116 colon carcinoma cells (wild-type53) compared to the isogenic HCT116p53-/- subline.

Keywords:  azide–alkyne (3+2) cycloaddition; glutarimide; imidazolones; spiroindolinones; thiohydantoin

DOI:  https://doi.org/10.3390/molecules31101602
Bioorg Chem. 2026 May 22. pii: S0045-2068(26)00554-7. [Epub ahead of print]179 110018

Antineoplastic multi-targeted spiro[indoline-3,2'-pyrrolidines] incorporating urea function: Rational design, synthesis and bio-properties studies.

Nehmedo G Fawzy, Siva S Panda, Mohamed S Bekheit, Walid Fayad, Ahmed A F Soliman, Adel S Girgis.

  The research study is dedicated towards synthesis of novel spiro[indoline-3,2'-pyrrolidines] incorporating a urea functionality. Crucially, the study seeks to elucidate their anticipated multi-targeted mechanism of action, moving towards the final objective of producing multi-functional antineoplastic agents. 1,3-Dipolar cycloaddition was used to construct the final compounds, the spiro-analogs 15a-m. 2-Propen-1-ones 12a-j provided a crucial part of the structure (the urea group). Isatins 13a,b and sarcosine 14, reacted together during the process to form in situ the necessary dipole, azomethine ylide. This synthetic protocol produced the targeted agents 15a-m with high yields. Biological evaluation identified compound 15l as a highly potent agent against the HCT116 colon cancer line, outperforming sunitinib and 5-fluorouracil by 3.7-fold and 7.9-fold, respectively. It is also identified with efficacy against MCF7 (breast cancer) close to that of 5-fluorouracil. Additionally, compound 15h exhibited exceptional potency against A431 skin squamous carcinoma surpassing 5-fluorouracil by 9.1-fold. Mechanistic studies confirmed the dual-action of rational design. Compound 15h demonstrated VEGFR-2 inhibition comparable to sorafenib, while 15g emerged as a dual MDM2 inhibitor and p53 activator, significantly outperforming doxorubicin. The correlation between MDM2 inhibition and p53 activation suggests that the disruption of the MDM2-p53 protein-protein interaction, alongside VEGFR-2 inhibition, drives the antiproliferative effects. Furthermore, compounds 15g, 15h, 15j, and 15k induced apoptosis through the upregulation of caspase-3 and BAX and the downregulation of Bcl-2. Cell cycle (flow cytometry) studies of 15h and 15j confirmed G0/G1 phase arrest. Moreover, the Annexin V-FITC/PI dual staining assay evidenced the apoptotic potential of compounds 15h and 15j. CAM assays supported the anti-angiogenic potential of 15g, 15h, 15j, and 15k. Finally, molecular docking (PDB ID: 5LAW) and dynamic simulations validated the binding stability and mechanism within the MDM2 pocket.

Keywords:  Cancer; MDM2-p53; Molecular docking; Spiro[indoline-3,2′-pyrrolidine]; Urea; VEGFR-2

DOI:  https://doi.org/10.1016/j.bioorg.2026.110018
J Mol Graph Model. 2026 May 22. pii: S1093-3263(26)00179-8. [Epub ahead of print]146 109453

Integrated multi-stage screening assisted discovery and optimization of spirooxindole MDM2 inhibitors.

Xuchen Xu, Kexin Cheng, Zigui Kan.

  The rational design of novel MDM2 inhibitors with superior biochemical properties represents the most consequential outcome of contemporary computer-aided drug discovery. Here, we report the discovery of spirooxindole-based p53-MDM2 interaction antagonists through a systematic, integrated multi-stage screening workflow that couples deep-learning-driven molecular remodeling with hierarchical physics-based assessment. Starting from 53 reported spirooxindoles, we first constructed a ligand-based pharmacophore model (ADHHR_1) and a validated PLS-5 3D-QSAR model (Q2 = 0.719) to quantify the microscopic contributions of hydrogen-bond donors, hydrophobic groups, and electron-withdrawing moieties to binding affinity. Leveraging the Modof graph-remodeling network trained on 1970 azaindoles, we generated 22 lead-like spirooxindole analogues (N01-N22). Hierarchical virtual screening via molecular docking identified 12 analogues surpassing the clinical reference Nutlin 3a in predicted affinity, the top candidate N14 achieved a binding energy of -9.2 kcal/mol versus -8.4 kcal/mol for Nutlin 3a. Sequential 500 ns molecular dynamics simulations, coupled with MM-PBSA free-energy decomposition, revealed that the N14@MDM2 complex possesses a markedly more favorable binding free energy (-41.5 kcal/mol) than Nutlin 3a (-35.42 kcal/mol), concomitant with enhanced conformational stability evidenced by lower backbone RMSD fluctuations and a tightly maintained radius of gyration. Per-residue interaction profiling further distinguished N14 by its unique contacts with Lys51 and His96, supplementing the shared hydrophobic anchor residues (Leu54, Ile61, Met62). Collectively, these biochemically supported findings nominate N14 as a priority lead with predicted advantages over the reference standard, establishing a generalizable AI-driven paradigm for protein-protein interaction inhibitor discovery that balances computational efficiency with predictive rigor.

Keywords:  Integrated multi-stage screening workflow; Spirooxindole; p53-MDM2

DOI:  https://doi.org/10.1016/j.jmgm.2026.109453
Oncogene. 2026 May 27.

MST4 plays dual roles in lung adenocarcinoma by regulating homeostasis of wild-type and mutant p53 protein.

Minghui Zhang, Changwei Hu, Huilong Liu, Chenxi Zhang, Qipeng Shu, Yu-Jian Kang, Yuetian Ding, Jin Zhang, Zhenghui Hu, Haokai Wang, Youfan Zhang, Ze-Yan Zhang, Shangze Li.

Mutations are highly prevalent in the TP53 tumor suppressor gene, which encodes p53, in lung adenocarcinoma (LUAD). However, targeted therapies centered on p53 mutations remain challenging. Here, we found MST4 highly expressed in LUAD and linked to patient survival. Functional assays using CRISPR-generated MST4-knockout LUAD cell lines revealed context-dependent dual roles of MST4: tumor-suppressive in wild-type p53 (wtp53) cells (inhibiting proliferation, colony formation, migration) and oncogenic in gain-of-function (GOF) p53 cells. Mechanistically, MST4 directly interacts with p53, competing with MDM2 to prevent K48-linked ubiquitination and degradation of both wtp53 and GOF-mutant p53, which explains cell-context-dependent phenotypes of MST4 suppression. Preclinically, targeting MST4 significantly repressed tumor formation of xenograft model with GOF-mutant p53. Collectively, our findings identify MST4 as a context-dependent regulator of LUAD, whose function is dictated by p53 mutation status. MST4 stabilizes p53 via a novel MDM2-competitive, kinase-independent mechanism, and targeting MST4 represents a promising therapeutic strategy for GOF-mutant p53-driven LUAD.

DOI: https://doi.org/10.1038/s41388-026-03824-7
Oncogene. 2026 May 24.

Liver-specific SIRT1 knockout-induced hyperglycemia promotes spontaneous lung adenocarcinomas through HSF1-MDM2.

Yiwei Cao, Jingyi Wei, Qiang Chen, Haitao Wang, Jiao Mu, Shuhan Lu, Menghui Yuan, Mohammed A El-Magd, Bichan Xu, Ruihong Wang, Peng Yuan.

Epidemiological studies have indicated a strong link between metabolic disease and an elevated risk of cancer. However, it has not been directly replicated in animal models, nor has its specific underlying mechanism been clarified. From our previous research, liver-specific SIRT1 knockout (LKO) mice developed hyperglycemia within two months and developed fatty liver with whole-body insulin resistance around nine months of age. When the mice's age extended to one year, they presented surprisingly higher lung tumor vulnerabilities in contrast to wild type as determined by macroscopic observation and histological examination. Interestingly, all lung tumors in these mice were classified as lung adenocarcinomas. Microarray analysis revealed elevated levels of MDM2, an oncoprotein, leading to the downregulation of its target genes such as p21 and GADD45. In vitro, the disruption of MDM2 leads to impaired cell cycle checkpoints and increased cell proliferation, which is accompanied by genomic instability, eventually causing full transformation in normal lung epithelia. In addition, the heat shock factor 1 (HSF1) transcription factor was found to regulate MDM2 directly and would decrease in the nucleus under high glucose conditions. Knockdown of HSF1 in the bronchial epithelial cell line (NL20) can increase MDM2 expression and cell proliferation. Human lung adenocarcinomas also displayed elevated MDM2 levels, with a correlation between MDM2 expression and lung cancer survival rates. Collectively, our findings suggest that liver-specific SIRT1 knockout-induced hyperglycemia promotes spontaneous lung adenocarcinomas through the HSF1-MDM2 pathway. Hyperglycemia may represent an underexplored cause of lung adenocarcinomas through impairment of cell cycle checkpoints, providing valuable insights for lung cancer prevention and future precision medicine.

DOI: https://doi.org/10.1038/s41388-026-03826-5
J Transl Med. 2026 May 26.

Molecular mechanisms underlying liposarcoma subtype transition and proteasome-associated targeted interventions.

Jiahao Liu, Mingke Huo, Sihan Wu, Zhen Wang, Sanfei Peng, Yang Fu.

   BACKGROUND: Liposarcoma (LPS) is one of the most common soft tissue sarcomas and is characterized by marked heterogeneity and a strong tendency toward recurrence. Conventional histopathologic classification mainly includes well-differentiated and dedifferentiated liposarcoma, myxoid and round cell liposarcoma, and pleomorphic liposarcoma. In recent years, molecular hallmarks, such as amplification of MDM2 and CDK4 and fusion genes including FUS::DDIT3 and CPSF6-related fusions, have become essential for accurate diagnosis and subtype assignment.
MAIN BODY: LPS development and subtype transition are driven by integrated molecular events, including 12q13-15 amplification with MDM2/CDK4 overexpression, PPARγ dysregulation, PI3K-AKT-mTOR activation, epigenetic alterations, and tumor microenvironment interactions. Together, these changes promote malignant transformation, dedifferentiation, and therapeutic heterogeneity across subtypes. Within this broader framework, the proteasome has emerged as a therapeutically relevant regulatory layer, particularly in selected contexts such as MDM2-amplified WDLS/DDLS, where protein turnover directly influences the stability of key driver proteins. Clinically, complete surgical resection remains the standard treatment when feasible, while doxorubicin plus ifosfamide is the mainstay for advanced or metastatic disease. Targeted therapies, such as palbociclib for MDM2-amplified WDLS/DDLS, as well as immunotherapy, have shown activity in some patients. Emerging investigational strategies also seek to target MDM2-p53, CDK4/6, epigenetic dysregulation, and proteostasis-related vulnerabilities.
CONCLUSION: This review summarizes the classification, subtype-specific characteristics, molecular mechanisms, treatment strategies, and prognosis of LPS, and further discusses how proteasome-associated mechanisms may create therapeutic vulnerabilities in selected subtypes. A better understanding of the molecular basis underlying tumor initiation, progression, and subtype transition may support the development of more precise and mechanism-based therapeutic strategies for LPS.

Keywords:  CDK4; Dedifferentiation; Liposarcoma; MDM2; Proteasome; Soft tissue sarcoma; Targeted therapy; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12967-026-08320-w
Clin Cancer Res. 2026 May 26.

A first-in-pediatric study of ALRN-6924, a novel stapled-peptide dual MDM2/MDMX inhibitor, for children with advanced hematologic and solid malignancies.

David S Shulman, Kieuhoa T Vo, Frank M Balis, Holly Lindsay, Bradley D DeNardo, Andrew E Place, Susan N Chi, Junne Kamihara, Allison F O'Neill, Alanna J Church, Brian D Crompton, Kelly Klega, Mohammad Tanhaemami, Myriam Armant, Yana Pikman, Kimberly Stegmaier, Suzanne Ezrre, Jeffrey Czaplinski, Loren D Walensky, D Allen Annis, Ketki Bhushan, Pei-Chi Kao, Wendy B London, Steven G Dubois.

PURPOSE: ALRN-6924 is a stapled peptide that disrupts MDM2/MDMX-mediated inhibition of p53. We evaluated safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ALRN-6924 in children with advanced malignancies.
EXPERIMENTAL DESIGN: Patients with TP53-wild-type malignancies were enrolled to a monotherapy arm (solid/CNS tumors) or combination arm with cytarabine (acute leukemia). Monotherapy dosing used the TARGET-CRM design for dose escalation. Pharmacodynamic assessment included serum MIC-1 as a biomarker of p53 activation. Circulating tumor DNA was analyzed for emergent TP53 mutations.
RESULTS: Twenty-two patients enrolled; 20 received treatment (17 monotherapy, 3 combination). The most common diagnosis was Ewing sarcoma (n=5). One dose-limiting toxicity (DLT) occurred at monotherapy dose level 2 (2.7 mg/kg). Six patients were treated at dose level 3 (3.5 mg/kg) without DLT, and one patient was treated at dose level 4 (4.3 mg/kg) without DLT before study closure. No DLTs occurred on the combination arm. Common treatment-related adverse events included anemia (90%) and nausea (70%). MIC-1 levels increased 30-50-fold by 24 hours post-dose at dose levels 2-4, confirming on-target p53 activation. Among 19 response-evaluable patients, one partial remission occurred in a patient with relapsed ALL on the combination arm. Drug exposure was lower than in adults at equivalent doses. One patient with Ewing sarcoma had an emergent TP53 mutation detected in their baseline on-therapy ctDNA sample.
CONCLUSIONS: ALRN-6924 was well tolerated in children with on-target activity. Future efforts to evaluate this agent should focus on biomarker-selected populations, combination strategies, and evaluation of higher dose levels.

DOI: https://doi.org/10.1158/1078-0432.CCR-26-0625