bims-midomi 2025-09-28 papers

bims-midomi

Biomed News

on MDM2 and mitochondria

Issue of 2025–09–28
six papers selected by
Gavin McStay, Liverpool John Moores University

Targeting p53-MDM2 pathway with novel triazole-oxazole hybrids: a fragment-based drug discovery approach for next-generation cancer therapies.
Immunohistochemical assessment of murine double minute 2 in solid vs unicystic ameloblastoma: A systematic review and meta-analysis.
Biodegradable Nanoparticles Encapsulating Murine Double Minute 2 siRNA to Treat Peritoneal Dissemination of Colon Cancer.
Study on the design, synthesis and activity of MDM2/MDMX anti-tumor stapled peptide PROTAC.
Primary cardiac endosarcoma: a case report.
Ipid nanomedicine simultaneously inhibits BRD4/PI3K and MDM2/XIAP signaling pathways for effective treatment of Medulloblastoma.

Mol Divers. 2025 Sep 23.

Targeting p53-MDM2 pathway with novel triazole-oxazole hybrids: a fragment-based drug discovery approach for next-generation cancer therapies.

Apurva Prajapati, Hitesh Patel.

  The tumor suppressor protein p53 plays a pivotal role in regulating key cellular processes, including cell cycle arrest, apoptosis, and DNA repair. Its negative regulator, MDM2, binds to the N-terminal domain of p53 and promotes its degradation, leading to the function inactivation of p53 in many cancers. Disrupting the p53-MDM2 interaction is thus an attractive therapeutic strategy, especially in tumors retaining wild-type p53. In this study, we applied a comprehensive in silico approach combining Fragment-Based Drug Discovery (FBDD), molecular docking, R-group enumeration, MM-GBSA binding energy estimation, ADMET prediction, MD simulations, DFT analysis to identify the novel p53-MDM2 inhibitors. Key findings demonstrated that the designed triazole-oxazole hybrids exhibited stable binding with critical MDM2 residues, improved solubility-driven pharmacokinetic behavior, and favorable electronic properties compared with reference inhibitor. Importantly, solubility-guided fragment design not only improved hit quality but also provided scaffolds with strong therapeutic potential. Overall, this study highlights triazole-oxazole hybrids as promising candidates for p53 reactivation and establishes a rational basis for their further biological evaluation in anticancer therapy.

Keywords:  Fragment-based drug discovery (FBDD); Triazole–oxazole hybrids; p53–MDM2 inhibitors

DOI:  https://doi.org/10.1007/s11030-025-11364-7
Arch Oral Biol. 2025 Sep 19. pii: S0003-9969(25)00228-6. [Epub ahead of print]180 106400

Immunohistochemical assessment of murine double minute 2 in solid vs unicystic ameloblastoma: A systematic review and meta-analysis.

Lilibeth-Stephania Escoto-Vasquez, Mario Alberto Alarcón-Sánchez, Julieta Sarai Becerra-Ruiz, Cristina Hermila Martínez-Bugarin, Sarah Monserrat Lomelí-Martínez, Armen A Muradyan, Artak Heboyan.

   OBJECTIVE: This project aimed to evaluate the immunoexpression pattern of murine double minute 2 (MDM2) in solid ameloblastomas compared to unicystic ameloblastomas.
METHODS: The review followed PRISMA guidelines and was registered in the PROSPERO database. PubMed, Scopus, ScienceDirect, Web of Science, and Google Scholar were comprehensively searched. Original cross-sectional studies were included. The meta-analysis was performed using STATA V15 and RevMan. Positivity rates were pooled using a random-effects model (REM), the labeling index was analyzed using mean difference under a REM, and expression intensity (moderate-strong) was assessed as categorical data using a REM with Hartung-Knapp adjustment. Heterogeneity was evaluated with the Chi² test and I² statistic. The methodological quality and certainty of the evidence were assessed using the Joanna Briggs Institute items and the GRADE system.
RESULTS: Nine studies (n = 438 specimens) were analyzed, of which 325/438 (74.2 %) were ameloblastoma biopsies. MDM2 positivity was detected in 403/438 cases (92 %). A statistically significant association in favor of solid ameloblastoma was observed (RR = 2.08; 95 %CI [1.66-2.60]; p = 0.005), indicating a twofold probability of finding high MDM2 expression in solid compared to unicystic ameloblastomas. Four of the nine studies (44.4 %) were considered to be of low quality, and the certainty of evidence was low to very low.
CONCLUSIONS: MDM2 expression was prevalent in both types of ameloblastomas, with a higher intensity of expression observed in solid cases. However, due to study heterogeneity, further investigations with more robust methodological designs are recommended to assess the diagnostic potential of MDM2 in ameloblastomas.

Keywords:  Immunohistochemistry; MDM2; Solid ameloblastoma; Unicystic ameloblastoma

DOI:  https://doi.org/10.1016/j.archoralbio.2025.106400
Int J Mol Sci. 2025 Sep 12. pii: 8883. [Epub ahead of print]26(18):

Biodegradable Nanoparticles Encapsulating Murine Double Minute 2 siRNA to Treat Peritoneal Dissemination of Colon Cancer.

Tomoaki Kurosaki, Akari Okada, Yuuki Takashima, Hitoshi Sasaki, Yukinobu Kodama.

  The study aim was to apply murine double minute 2 (MDM2)-siRNA to a biodegradable siRNA delivery vector, ternary complex, for treating colorectal cancer peritoneal dissemination. The ternary complex containing MDM2-siRNA (MDM2-siRNA complex) was constructed by mixing MDM2-siRNA, dendrigraft poly-L-lysine, and γ-polyglutamic acid. Cellular uptake of the ternary complex and suppressive effect on MDM2-mRNA were determined in a mouse colorectal cancer cell line. Tumor-growth inhibition by the MDM2-siRNA complex was evaluated in peritoneal dissemination model mice. The MDM2-siRNA complex, with an approximately 177 nm particle size and -35 mV ζ-potential, prevented degradation of the inner siRNA by RNase. In the in vitro study, the ternary complex was highly taken up by the cells, and 2 μg/mL of the MDM2-siRNA complex significantly decreased MDM2-mRNA to about 30% of control cells. Intraperitoneal administration in colorectal cancer peritoneal dissemination model mice showed little effect of the ternary complex containing scramble-siRNA on cancer growth in the peritoneal cavity. Conversely, the MDM2-siRNA complex significantly reduced peritoneal dissemination to less than 1/1000th of control mice and successfully prolonged survival time. In this study, we found that the biodegradable MDM2-siRNA complex had a suppressive effect on MDM2-mRNA in cancer cells and tumor growth of peritoneal dissemination.

Keywords:  biodegradable nanoparticles; colorectal cancer peritoneal dissemination; murine double minute 2; siRNA delivery system

DOI:  https://doi.org/10.3390/ijms26188883
Sci Rep. 2025 Sep 25. 15(1): 32923

Study on the design, synthesis and activity of MDM2/MDMX anti-tumor stapled peptide PROTAC.

Xiufei Liao, Mao Guo, Damin Hu, Chunli Su, Hongli Liao.

  PROTAC is a drug development technology that uses the Ubiquitin-Proteasome System (UPS) to degrade target proteins, and enhances the degradation ability of target proteins through E3 ubiquitin ligase, which can further enhance the anti-tumor effect of targeted drug molecules. In this study, a series of dual-target MDM2/MDMX stapled peptide PROTAC based on SM3-4 were designed and synthesized, and the stapled peptide PROTAC DSM3-2 and DSM3-5 screened in the study inhibited tumor cell growth in vitro at low µM concentrations. The results showed that the enhancement of stapled peptide activity was positively correlated with the increase of helicity, which provided an effective research basis for the dual-target anti-tumor stapled peptide PROTAC. Molecular docking experiments have shown that the binding peptide DSM3-2 can effectively bind to the target proteins MDM2 and MDMX to exert a dual targeting effect on tumor cells.

Keywords:  Anti-tumor; PROTAC; Stapled peptides

DOI:  https://doi.org/10.1038/s41598-025-18026-6
J Med Case Rep. 2025 Sep 26. 19(1): 447

Primary cardiac endosarcoma: a case report.

Shishi Zhong, Yanhong Luo, Yunxia Fei, Siyu Zhang.

   BACKGROUND: Primary cardiac intimal sarcoma is an exceptionally rare and aggressive malignancy, representing a small subset of primary cardiac tumors. Owing to its rapid progression and limited treatment options, the median survival is typically less than 1 year. We report a rare case of primary cardiac intimal sarcoma with MDM2 amplification, in which the patient achieved survival exceeding 1 year through a multimodal treatment approach, offering valuable insights into the management of this highly lethal disease.
CASE PRESENTATION: A 48-year-old previously healthy Han Chinese woman presented with progressive chest tightness, dyspnea, and hemoptysis. Imaging revealed a large, irregular mass (64 × 41 mm) in the left atrium, partially prolapsing into the left ventricle. Elevated serum tumor markers were noted. The patient underwent surgical resection under cardiopulmonary bypass, and histopathological examination confirmed intimal sarcoma with MDM2 gene amplification. The diagnosis is: primary cardiac endosarcoma. Despite postoperative recurrence within the left ventricle, sequential therapies were implemented, including liposomal doxorubicin, oral anlotinib, and combined chemotherapy with gemcitabine and docetaxel plus anlotinib. The tumor initially showed progression but subsequently demonstrated partial regression following therapy adjustments. The patient has remained clinically stable for over 1 year post-diagnosis under ongoing treatment.
CONCLUSION: This case highlights the extreme rarity and poor prognosis of primary cardiac intimal sarcoma and demonstrates that combining surgery, chemotherapy, and targeted therapy may contribute to prolonged survival. These findings suggest the potential role of anlotinib-based therapy for managing MDM2-amplified cardiac intimal sarcoma and warrant further clinical investigation.

Keywords:  Cardiac sarcoma; Cardiac ultrasonography; Pathology; Surgical excision of tumors; Systemic chemotherapy

DOI:  https://doi.org/10.1186/s13256-025-05538-y
J Control Release. 2025 Sep 24. pii: S0168-3659(25)00878-8. [Epub ahead of print] 114266

Ipid nanomedicine simultaneously inhibits BRD4/PI3K and MDM2/XIAP signaling pathways for effective treatment of Medulloblastoma.

Bharti Sethi, Aditya Gupta, Qiaoyu Pan, Sohan Mahto, Ajaykumar Chittipolu, Helen Erickson, Virender Kumar, Yanfei Chen, Zhongzhi Wu, Yuxiang Dong, Wei Li, Donald R Ronning, Donald W Coulter, Ram I Mahato.

  Medulloblastoma (MB) is the most common childhood brain tumor arising from the cerebellum. PI3K and BRD4 signaling pathways are known to induce MB cell growth, cancer stem cell (CSC) proliferation, and tumor resistance. Further, the tumor suppressor gene TP53 is found to be inactivated in MB due to overexpression of its negative regulator MDM2. In this study, we synthesized MDP5, a potent BRD4/PI3K dual inhibitor, and JW475A, a potent dual MDM2 and XIAP inhibitor. The combination of these two drugs significantly decreased the colony formation capacity compared to individual drugs. Given the challenge of inefficient drug transport across the blood-brain barrier (BBB), we prepared rabies virus glycoprotein (RVG) peptide decorated lipid nanoparticles (LNPs), which showed 4.9 ± 0.1 and 4.8 ± 0.1 % loading for MDP5 and JW475A, respectively. In vivo studies in mice showed that Cy5.5 labeled RVG-LNPs were detected in the brain after systemic administration. Combination drug-loaded RVG-LNPs significantly decreased the MB growth in orthotopic mouse model of MB compared to free drug combination and non-targeted LNPs. This study indicates that MDP5 and JW475A -loaded RVG-LNPs are a promising drug brain delivery system worth exploring further in clinical settings for MB therapy.

Keywords:  BRD4; JW475A; LNPs; MDP5; Medulloblastoma; PI3K; RVG-peptide

DOI:  https://doi.org/10.1016/j.jconrel.2025.114266