bims-midomi Biomed News
on MDM2 and mitochondria
Issue of 2025–07–20
six papers selected by
Gavin McStay, Liverpool John Moores University
  1. Brigimadlin (BI-907828) and napabucasin (BBI608) cooperatively trigger apoptosis in chronic lymphocytic leukemia cells by simultaneous iİnhibition of MDM2 and STAT3.
  2. Anticancer Quinolinol Small Molecules Target Multiple Pathways to Promote Cell Death and Eliminate Melanoma Cells Resistant to BRAF Inhibitors.
  3. A case report and literature review on a large MDM2 negative retroperitoneal/psoas muscle well-differentiated liposarcoma mimicking intramuscular myxoma.
  4. hMTR4 promotes p53 protein degradation and tumor growth by accelerating rRNA processing and regulating the RPL5-MDM2 axis.
  5. Microscopic Insights into the Solvation of Stapled Peptides-A Case Study of p53-MDM2.
  6. Prognostic Implications of MDM2 and CDK4 Co-amplification in Liposarcoma: Insights from FISH analysis for Translational Oncology.
  1. Mol Biol Rep. 2025 Jul 17. 52(1): 731
    Brigimadlin (BI-907828) and napabucasin (BBI608) cooperatively trigger apoptosis in chronic lymphocytic leukemia cells by simultaneous iİnhibition of MDM2 and STAT3.
    Erhan Aptullahoglu.
       BACKGROUND: Chronic lymphocytic leukemia (CLL) remains largely incurable, particularly in elderly or treatment-resistant patients. Although MDM2 inhibitors restore p53-mediated apoptosis in p53-functional CLL, single-agent activity is limited by resistance mechanisms. Signal transducer and activator of transcription 3 (STAT3) signaling also promotes CLL survival and immune evasion, suggesting that concurrent blockade of both pathways may enhance cell death.
    METHODS AND RESULTS: Here, the synergistic potential of the oral MDM2 antagonist BI-907828 (brigimadlin) and the STAT3 inhibitor BBI608 (napabucasin) was evaluated in two CLL cell lines with distinct TP53 (Tumor Protein p53, the gene encoding p53 protein) status: p53-wild-type EHEB and p53-mutant/17p-deleted MEC-1. Monotherapy with BI-907828 induced marked p53 stabilization, upregulation of p21WAF1, PARP cleavage, and caspase-3/7 activation in EHEB cells, whereas MEC-1 cells remained unresponsive. BBI608 alone reduced cell viability in both lines in a dose-dependent manner, with its effect in MEC-1 cells suggesting a p53-independent mechanism. When combined, BI-907828 and BBI608 synergistically enhanced apoptotic markers in EHEB cells (δ synergy score > 17) but elicited no synergy in MEC-1, underlining the requirement for intact p53.
    CONCLUSION: These findings establish a mechanistic rationale for the concurrent targeting of the MDM2 and STAT3 axes and provide preclinical evidence for a promising, non-genotoxic therapeutic strategy in p53-functional CLL. A limitation of this study is the lack of in vivo validation and clinical data, which are necessary to further assess the safety, optimal dosing, and efficacy, particularly in elderly or unfit patients with limited treatment options.
    Keywords:  Brigimadlin (BI 907828); Chronic lymphocytic leukaemia; MDM2-p53 antagonists; Napabucasin (BBI608); STAT3
    DOI:  https://doi.org/10.1007/s11033-025-10834-3
  2. Molecules. 2025 Jun 22. pii: 2696. [Epub ahead of print]30(13):
    Anticancer Quinolinol Small Molecules Target Multiple Pathways to Promote Cell Death and Eliminate Melanoma Cells Resistant to BRAF Inhibitors.
    Xinjiang Wang, Rati Lama, Alexis D Kelleher, Erika C Rizzo, Samuel L Galster, Chao Xue, Yali Zhang, Jianmin Wang, Jun Qu, Sherry R Chemler.
      Small molecule inhibitors that target the E3 ligase activity of MDM2-MDM4 have been explored to inhibit the oncogenic activity of MDM2-MDM4 complex. MMRi62 is a small molecule that was identified using an MDM2-MDM4 E3 ligase-based high throughput screen and a cell-death-based secondary screen. Our previous studies showed that MMRi62 promotes MDM4 degradation in cells and induces p53-independent apoptosis in cancer cells. However, MMRi62 activity in solid tumor cells such as melanoma cells, especially in BRAF inhibitor resistant melanoma cells, have not been explored. Although its promotion of MDM4 degradation is clear, the direct MMRi62 targets in cells are unknown. In this report, we show that MMRi62 is a much more potent p53-independent apoptosis inducer than conventional MDM2 inhibitors in melanoma cells. A brief structure-activity study led to development of SC-62-1 with improved activity. SC-62-1 potently inhibits and eliminates clonogenic growth of melanoma cells that acquired resistance to BRAF inhibitors. We developed a pair of active and inactive SC-62-1 probes and profiled the cellular targets of SC-62-1 using a chemical biology approach coupled with IonStar/nano-LC/MS analysis. We found that SC-62-1 covalently binds to more than 15 hundred proteins in cells. Pathways analysis showed that SC-62-1 significantly altered several pathways including carbon metabolism, RNA metabolism, amino acid metabolism, translation and cellular response to stress. This study provides mechanistic insights into the mechanisms of action for MMRi62-like quinolinols. This study also suggests multi-targeting compounds like SC-62-1 might be useful for overcoming resistance to BRAF inhibitors for improved melanoma treatment.
    Keywords:  E3 ligase; MDM2-MDM4; MMRi62; cell death; chemical robe; quinolinol; targets
    DOI:  https://doi.org/10.3390/molecules30132696
  3. Radiol Case Rep. 2025 Sep;20(9): 4661-4668
    A case report and literature review on a large MDM2 negative retroperitoneal/psoas muscle well-differentiated liposarcoma mimicking intramuscular myxoma.
    Victoria Xie, Guiliang Yu, Amanda Wiggett, Justin Rivard, Miao Lu, Yi Yan.
      Well-differentiated liposarcoma (WDLPS) typically presents as a large soft tissue mass in the retroperitoneal region. Amplification of the MDM2 gene is considered the gold standard for pathologic diagnosis. We present a case of 22 cm large intramuscular mass, located in the psoas muscle of the retroperitoneum. No macroscopic fat was identified on imaging, and the lesion featured extensive myxoid stroma, closely mimicking an intramuscular myxoma on both radiological and histopathological evaluation from biopsy sample. Final diagnosis was however revised to MDM2-negative WDLPS. This case highlights the diagnostic challenge posed by WDLPS with extensive myxoid stroma lacking MDM2 amplification and macroscopic fat on imaging. Accurate diagnosis relies on the integration of clinical, radiologic, and pathologic data, as well as thorough sampling of the tumor.
    Keywords:  Intramuscular myxoma; Myxoid neoplasm, Core biopsy, MDM2 gene; Well-differentiated liposarcoma
    DOI:  https://doi.org/10.1016/j.radcr.2025.05.094
  4. Cell Death Differ. 2025 Jul 13.
    hMTR4 promotes p53 protein degradation and tumor growth by accelerating rRNA processing and regulating the RPL5-MDM2 axis.
    Chen Xie, Xin-Ling Liang, Bin Chen, Sui Chen, Fang-Xin Xiong, Qi-Cheng Wang, Zhan-Li Chen, Feng-Jun He, Yihang Pan, Shi-Mei Zhuang.
      hMTR4 is an RNA helicase and an essential co-factor for the nuclear RNA exosome. Its role in the p53 pathway and cell cycle control remains unknown. Here, gain- and loss-of-function analyses in cell models showed that hMTR4 could not affect p53 mRNA levels, but decreased the levels of p53 protein and its downstream target genes by promoting p53 ubiquitination and degradation, thus accelerating cell cycle progression. These effects of hMTR4 were abrogated by nutlin-3A, an inhibitor of E3 ligase MDM2. Mechanistically, hMTR4 promoted rRNA processing in an RNA helicase-dependent manner, thus increased the amount of mature rRNA to bind ribosomal protein L5 (RPL5), resulted in sequestration of RPL5 in the nucleolus and reduced binding of RPL5 to MDM2 in the nucleoplasm, consequently promoted MDM2-mediated degradation of p53 protein. Silencing RPL5 blocked the effect of hMTR4 knockdown in upregulating p53, while hMTR4 overexpression abrogated the role of RPL5 in stimulating p53 activity. Interestingly, hMTR4 reduced the mRNA levels of p53-target genes via repressing p53 activity rather than promoting their RNA degradation. These findings disclose a novel hMTR4-rRNA-RPL5-MDM2-p53 axis and highlight hMTR4 and rRNA processing as important regulators of the p53 pathway. Further investigations on clinical samples showed that hMTR4 and RPL5 were frequently upregulated in different malignancies, including hepatocellular carcinoma (HCC), and they exhibited a positive correlation. High hMTR4 level was correlated with high recurrence of HCC, among patients with high RPL5 levels and wildtype p53 in tumors. Studies using mouse xenograft models revealed that silencing Skiv2l2 (the homologue of human hMTR4) in mouse hepatoma cells inhibited xenograft development, and tumor growth was suppressed by intratumoral injection of antisense oligonucleotides (ASO) targeting Skiv2l2. These data suggest the significance of hMTR4 overexpression in promoting tumor growth and its potential as a therapeutic target.
    DOI:  https://doi.org/10.1038/s41418-025-01541-4
  5. J Phys Chem B. 2025 Jul 15.
    Microscopic Insights into the Solvation of Stapled Peptides-A Case Study of p53-MDM2.
    Vikram Gaikwad, Asha Rani Choudhury, Rajarshi Chakrabarti.
      Water, often termed the universal solvent, plays a vital role in numerous biomolecular processes, including protein-protein interactions. These interactions are frequently mediated by water molecules, making their characterization essential for developing therapeutic strategies. One such critical complex is p53-MDM2, which is central to cellular regulation. Inhibiting the p53-MDM2 interaction remains a significant therapeutic challenge, and stapled peptides have emerged as promising candidates in this context. The stapled peptides are peptidomimetics in which the side chains of two suitably positioned amino acids are covalently linked using an appropriate chemical moiety. In this study, we investigate the role of water in the binding of stapled p53 peptides to MDM2 using extensive molecular dynamics simulations. Our aim is to understand how variations in the chemical nature and stapling position of the hydrocarbon cross-linker influence the behavior of water molecules surrounding the p53 peptide. We demonstrate that such modifications significantly alter the structure and dynamics of the surrounding solvent. Using rigorous entropy calculations, we rationalize the enhanced binding affinity of stapled p53 peptides compared to that of their unstapled counterparts from a solvent-centric perspective. Specifically, the entropy gain of water molecules around the stapled peptides, combined with the conformational entropy loss of the peptide, contributes favorably to binding. These findings offer valuable insights into the rational design of stapled peptides and support the development of improved therapeutic inhibitors targeting the p53-MDM2 interaction.
    DOI:  https://doi.org/10.1021/acs.jpcb.5c03100
  6. Clin Transl Oncol. 2025 Jul 16.
    Prognostic Implications of MDM2 and CDK4 Co-amplification in Liposarcoma: Insights from FISH analysis for Translational Oncology.
    Jessinntha James, Aidy Irman Yajid, Sahran Yahaya, Sarimah Abdullah, Sharifah Emilia Tuan Sharif.
       PURPOSE: MDM2 and CDK4 amplifications are well-established diagnostic markers in liposarcoma, but the clinical relevance of their co-amplification remains underexplored. This study evaluates their amplification characteristics and combined prognostic impact to inform risk stratification and patient management.
    METHODS: Fluorescence in situ hybridisation (FISH) was performed on formalin-fixed paraffin-embedded samples of liposarcoma or benign lipomatous tumours (≥ 10 cm) histologically diagnosed at Hospital Pakar Universiti Sains Malaysia. Recurrence-free (RFS) and metastasis-free survival (MFS) across amplifications were determined using Kaplan-Meier. Recurrence associations with clinicopathological variables were examined using Cox regression.
    RESULTS: Among 86 cases, 27% were liposarcoma and 73% were benign tumours by FISH. Co-amplification (13%) was observed in all dedifferentiated liposarcoma (DDLS) and half of atypical lipomatous tumour/well-differentiated liposarcoma (ALT/WDLS) cases. MDM2 amplification without CDK4 (6%) was seen in ALT. Myxoid liposarcoma, pleomorphic liposarcoma, and benign tumours showed no amplification (81%). DDLS had higher MDM2 and CDK4 amplification ratios (4.4 and 2.8, respectively) than ALT/WDLS (2.9 and 2.6, respectively), with MDM2 consistently exceeding CDK4. Co-amplification associated with the shortest median RFS (34 months; p = 0.002) and MFS (83 months; p = 0.003). Surgery with chemotherapy (p = 0.042; HR = 26.50) associated with recurrence, while MDM2/CDK4 amplification was not an independent prognostic factor.
    CONCLUSION: MDM2 amplification was more consistent and quantitatively higher than CDK4, supporting its central role in tumourigenesis. While MDM2/CDK4 co-amplification was associated with poorer outcomes, it lacked independent prognostic value, reflecting the potential influence of other clinical variables. Nevertheless, co-amplification may hold clinical relevance in identifying high-risk liposarcoma subgroups.
    Keywords:   CDK4 amplification; MDM2 amplification; FISH; Liposarcoma; Translational oncology
    DOI:  https://doi.org/10.1007/s12094-025-03989-9
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