bims-midomi 2026-06-28 papers

Proc Natl Acad Sci U S A. 2026 Jun 30. 123(26): e2611131123

MDM2 suppresses c-Myc synthesis by binding to the 5' mRNA translation regulatory sequence.

Justine Habault, Norman Salomao, Lixiao Wang, Laurence Malbert-Colas, Chrysoula Daskalogianni, Sivakumar Vadivel Gnanasundram, Mitesh Dongre, Marzia Spagnardi, Lucia Martinkova, Sa Chen, Lenka Hernychová, Lucas Robidas, Josef Kucera, Ondřej Bonczek, Daniel Öhlund, Michael J Garabedian, Susan K Logan, Borek Vojtesek, Robin Fahraeus.

The p53 tumor suppressor and the c-Myc oncogene are among the most frequently deregulated genes in human cancers, yet the molecular cross talk between these pathways remains poorly understood. MDM2 is a key negative regulator of p53 and a target for emerging cancer therapies designed to activate p53. Likewise, targeting c-Myc is a long-standing but challenging goal in cancer therapy. Here, we report that the small MDM2-binding drug Milademetan promotes an interaction between MDM2 and the 5' untranslated region of the c-Myc mRNA, causing a suppression of c-Myc mRNA translation without affecting c-Myc RNA levels. The interaction also occurs under nonproliferative conditions in the absence of drug. Milademetan-mediated c-Myc depletion is accompanied by the induction of apoptosis and suppression of cell proliferation and prevents tumor growth, independently of p53 status. These findings reveal an unexpected mechanism by which MDM2 coordinates two of the most frequently altered pathways in cancer and provide a rationale for targeting c-Myc-driven tumors, including those lacking functional p53, through MDM2 modulators.

Keywords: MDM2-RNA interaction; c-MYC; p53; translation control; tumor heterogeneity

DOI: https://doi.org/10.1073/pnas.2611131123

Cancer Sci. 2026 Jun 26.

A Three-Dimensional Culture-Drug Sensitivity Test Predicts MDM2 Inhibitor-Sensitivity in SMARCB1/INI1-Deficient Tumors.

Hiroaki Goto, Chiyoko Nishime, Takashi Ohtsu, Mieko Ito, Maiko Sagisaka, Takuya Naruto, Norihiko Kitagawa, Mio Tanaka, Masakatsu Yanagimachi, Yukihiko Hiroshima, Junko Takita, Yasuhide Hayashi, Yohei Miyagi.

Loss of SMARCB1/INI1 expression is a common feature of various types of tumors including malignant rhabdoid tumor, an aggressive cancer of children. Because SMARCB1/INI1 deficiency leads to genome-wide transcriptional dysregulation, identifying a specific therapeutic target that acts on a wide range of SMARCB1/INI1-deficient tumors has been challenging. This study aimed to establish if the personalized selection of effective drugs against SMARCB1/INI-deficient tumors is possible by in vitro drug sensitivity profiling. The in vitro drug sensitivity profiles of tumors from SMARCB1/INI1-deficient tumor cell line-derived mouse xenograft (CDX) models were evaluated by a short-term collagen gel-embedded three-dimensional culture-drug sensitivity test (3D-DST). With the 3D-DST, molecular targeting drugs, including inhibitors of aurora B kinase, mammalian target of rapamycin, mitogen-activated protein kinase, WNT/β-catenin, or mouse double minute 2 homolog (MDM2), were selected as therapeutic drug candidates in SMARCB1/INI1-deficient tumors. A CDX tumor, which was resistant to MDM2 inhibitors in the 3D-DST, expressed lower TP53 compared to an MDM2 inhibitor-sensitive tumor. In cultured cell lines, exposure to MI-773, a MDM2 inhibitor, disturbed the expression of a significant number of genes and induced p21 protein expression in MDM2 inhibitor-sensitive cells. However, such changes were not observed in resistant cells. These results suggest that 3D-DST can predict biologically relevant drug sensitivity profiles in SMARCB1/INI1-deficient tumors.

Keywords: INI1; MDM2 inhibitor; SMARCB1; in vitro drug sensitivity test; three‐dimensional culture

DOI: https://doi.org/10.1111/cas.70451

Pharmaceuticals (Basel). 2026 May 22. pii: 814. [Epub ahead of print]19(6):

Discovery of Benzophenanthridine Alkaloids from Zanthoxylum nitidum That Target the MDM2-p53 Axis in NSCLC.

Nguyen Manh Cuong, Elizaveta Fefilova, Vu Thanh Loc, Natalia Karpova, Nguyen Xuan Ha, Alexandra Daks, Nguyen Viet Ha, Tran Thu Huong, Sergey Parfenyev, Alexander Nazarov, Oleg Semenov, Yulia Gnennaya, Olga Fedorova, Nickolai A Barlev, Oleg Shuvalov.

Background/Objectives: Non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancers and is a leading cause of cancer-related deaths worldwide. Pharmacological targeting of the p53-MDM2 interaction to activate wild-type p53 is a promising strategy for treating NSCLC that retain functional p53 (approximately 50% of all cases). Methods: We screened 33 ethnomedicinal Vietnamese plant extracts for their anticancer effects using p53-expressing and p53-null NSCLC cell models, as well as two non-cancerous cell lines for control. We used an array of different experimental approaches including NMR spectroscopy; molecular docking; an MTT test; cell cycle analysis; apoptosis analysis; wound healing, migration, and invasion assays; Real-Time PCR; immunoblotting; and Seahorse energy profiling to characterize and study the effects of these bioactive compounds on NSCLC cells. Results: Ethanol extract of Zanthoxylum nitidum stems and twigs demonstrated potent and selective activity by inducing p53-dependent cell cycle arrest and apoptosis. Phytochemical analysis identified several benzophenanthridine alkaloids as active constituents. Molecular docking revealed their strong in silico binding to MDM2. Notably, nitidine was the most promising compound among the molecules tested. Unlike nutlin, but similar to SP141 (two well-known MDM2 inhibitors), nitidine strongly stabilized p53 while concomitantly attenuating MDM2 at the protein level. Surprisingly, this effect was p53-independent. Additionally, nitidine suppressed the EMT master regulator Snail, and hence disrupted cellular bioenergetics and inhibited migration and invasion of NSCLC cells. Conclusions: Our findings identify Z. nitidum and nitidine as promising sources for developing novel MDM2-targeting therapeutics against NSCLC irrespective of the p53 status.

Keywords: 8-acetonyldihydrochelerythrine; MDM2; NSCLC; Zanthoxylum nitidum (Roxb.) DC.; metabolic rewiring; nitidine; p53; sanguinarine; snail; terihanine

DOI: https://doi.org/10.3390/ph19060814

Pharmacol Res. 2026 Jun 20. pii: S1043-6618(26)00229-X. [Epub ahead of print]230 108314

PET radiotracers targeting MDM2 protein interaction: From preclinical validation to first-in-human studies.

Chengxue He, Zhen Wang, Nina Zhou, Xiangxi Meng, Hua Zhu, Chunyi Hao, Zhi Yang, Lei Xia.

Current imaging techniques inadequately delineate surgical margins of well-differentiated liposarcoma (WDLS), increasing risks of incomplete resection or overtreatment. MDM2, a p53-inhibiting oncoprotein amplified in WDLS, represents a dual diagnostic and therapeutic target. Therefore, we developed two radionuclide probes utilizing the MDM2-targeting stapled peptide with high binding affinity to evaluate their suitability for tumor-specific diagnostic purposes, which named [68Ga]Ga-DOTA-7041 and [68Ga]Ga-DOTA-P53-8 to conduct a head-to-head comparative study. Among these, [68Ga]Ga-DOTA-7041 showed superior MDM2-binding affinity (6.7 nM). In vivo imagery in ccRCC tumor-bearing PDX models showed significant and rapid uptake for both radiotracers, with specific radioactive accumulation beginning at 10 min and persisting over time. In contrast, the SW872 liposarcoma mouse model demonstrated slower and lower uptake, visible at 4 h in PET/CT scans. The further Clinical PET/CT in a WDLS patient using the superior probe [68Ga]Ga-DOTA-7041 showed heterogeneous tumor uptake, correlating with postoperative MDM2 immunohistochemistry. In this study, [68Ga]Ga-DOTA-7041 demonstrated diagnostic potential in both animal models and patients with liposarcoma as first-in-human PET tracer targeting MDM2. The disparate tumor uptake observed, compared to the high uptake in renal cancer models, may provide valuable insights into the challenges of targeting MDM2/MDMX with therapeutic agents in liposarcoma treatments.

Keywords: Diagnosis; Liposarcoma; MDM2; PET/CT imaging; Stapled peptide; [(68)Ga]Ga-DOTA-7041

DOI: https://doi.org/10.1016/j.phrs.2026.108314