bims-midomi 2026-04-12 papers

Eur J Med Chem. 2026 Mar 29. pii: S0223-5234(26)00248-5. [Epub ahead of print]311 118803

Synthesis and evaluation of RG7388-based fluorinated MDM2 inhibitors for developing 18F-labeled probes for PET imaging.

Atchimnaidu Siriki, Zhengyuan Zhou, Graham Ragland, Satish K Chitneni.

MDM2 (murine double minute 2) is a negative regulator of the tumor suppressor protein p53 and is frequently overexpressed in sarcomas. MDM2 inhibition with small-molecule and peptide inhibitors has been shown to increase p53 levels and induce therapeutic effects in wild-type p53 cancer cells. MDM2 is considered a promising drug target, with several MDM2 inhibitors currently in clinical development. Hence, a noninvasive imaging tool to evaluate MDM2 expression in tumors would be highly valuable for guiding MDM2-targeted therapies. Herein, we report the synthesis and preliminary evaluation of RG7388-based fluorinated MDM2 inhibitors as potential 18F-labeled PET probes for imaging MDM2. RG7388 was modified at the carboxylic acid or methoxy functions to synthesize 3 fluorinated analogues for each series. Based on inhibition data and their comparable potency (IC50) towards MDM2, we selected RG7388 analogues 1 and 6, both bearing a fluoroethyl-1,2,3-triazole moiety, for 18F-labeling via click chemistry. From these studies, the carboxy-modified [18F]1 was identified as a promising lead compound, with an IC50 of 16.8 nM and high uptake and specificity in MDM2-expressing osteosarcoma cell lines, SJSA-1 and U2OS. [18F]1 showed favorable biodistribution characteristics in healthy mice, and preliminary PET/CT imaging studies revealed a higher uptake of [18F]1 in SJSA-1 xenografts compared to muscle at 1 h post-injection. Western blot analysis of SJSA-1 cells and immunohistochemical staining of SJSA-1 tumor sections confirmed high MDM2 expression and its localization in the nuclei of tumor cells, corroborating the PET imaging data.

Keywords: Fluorine-18; MDM2; PET imaging; RG7388; Sarcoma; p53

DOI: https://doi.org/10.1016/j.ejmech.2026.118803

J Adv Res. 2026 Apr 06. pii: S2090-1232(26)00302-4. [Epub ahead of print]

GL-V9 disrupts the mitochondrial homeostasis and triggers the integrated stress response by promoting the binding of cytosolic MDM2 with NDUFS1 in colorectal cancer.

Yibo Zhang, Chen Xun, Chenxiao Shi, Rui Wang, Yuan Gao, Di Pan, Yongjian Guo, Libin Wei.

INTRODUCTION: The oncogenic role of mouse double minute 2 (MDM2) is primarily attributed to its regulation of p53-dependent signaling cascades. The colorectal cancer (CRC) remains in the top five most prevalent and lethal cancers. P53 mutations are detected in 45-50% of CRC, leading to the failure of such MDM2 inhibitors in clinical trials.
OBJECTIVES: Small molecular compound GL-V9 targets MDM2 and leads a non-canonical function of MDM2 mediated anti-CRC effects.
METHODS: Interaction of MDM2 with NDUFS1 as well as the mitochondrial location of NDUFS1 were assessed by a pull-down assay and immunofluorescence analysis. The binding of GL-V9 to MDM2, was analyzed by molecular docking, cellular thermal shift assay (CESTA), surface plasmon resonance (SPR), GST-pulldown and amino acid mutations. Mitochondrial homeostasis was evaluated by mitochondrial membrane potential, mitochondrial superoxide, ATP generation and oxygen consumption rate.
RESULTS: Different from MDM2 inhibitors, GL-V9 binds to the MDM2 amino-terminal domain (amino acids 1-101) and facilitates the interaction of MDM2 with NDUFS1 in cytoplasm through a p53-independent manner, instead of disruption of p53-MDM2 binding or the promotion of MDM2 protein degradation. This process additionally inhibits the formation of electron transport chain complex I and disrupts the mitochondrial homeostasis, which finally activates OMA1-DELE1 signaling axis and induces the integrated stress response (ISR)-triggered apoptosis.
CONCLUSION: This study provides a novel candidate for CRC therapy with favorable safety profile. Importantly, the novelty mode of action by GL-V9, working as molecular glue for MDM2/NDUFS1, provides a new insight for targeting MDM2 regardless of p53 status.

Keywords: Colorectal cancer; GL-V9; Integrated stress response; MDM2-NDUFS1 interaction; Mitochondrial homeostasis

DOI: https://doi.org/10.1016/j.jare.2026.04.019

Sci Rep. 2026 Apr 06.

RNA-based next-generation sequencing strategy for screening MDM2-amplified sarcomas.

Cheng Lei, Hongjing Zang, Haixia Zhang, Yu He, Min Zhang, Yi Sun, Songqing Fan, Peng Zhou.

The accurate diagnosis of soft tissue sarcomas and bone tumors poses persistent challenges in pathological practice. While targeted RNA-based next-generation sequencing (NGS) has enhanced diagnostic precision through fusion gene detection, its clinical utility remains limited for dedifferentiated liposarcoma (DDLPS) due to the inability to identify MDM2 copy number variations - a critical diagnostic feature. This limitation is particularly clinically relevant as morphologically atypical DDLPS cases may undergo targeted RNA NGS testing. Through retrospective analysis of 150 patients undergoing RNA NGS and validation with TCGA-SARC data, we developed a novel screening algorithm for DDLPS using RNA NGS data, specifically the number of fusion events within the 12q13-15 chromosomal region and MDM2 transcript levels. Both metrics were significantly elevated in DDLPS compared to non-DDLPS cases in our institutional cohort (p < 0.001). ROC analysis established optimal diagnostic thresholds: ≥3 fusions in 12q13-15 region achieved 100% sensitivity (95% CI: [73.53%-100%]; 12/12) and 95.65% specificity (95% CI: [90.78%-98.39%]; 132/138). Similarly, MDM2 RNA expression ≥ 100 TPM showed 100% sensitivity (95% CI: [63.1%-100%]; 8/8) and 97.37% specificity (95% CI: [90.8%-99.7%]; 74/76). The algorithm also performed robustly in the TCGA-SARC data, although with a slightly different optimal cutoff, likely due to differences in gene panels, depth of sequencing, gene coverage, and bioinformatics pipelines. This study presents an effective strategy for screening DDLPS and potentially other MDM2-amplified sarcomas.

Keywords: DDLPS; Fusion; MDM2; RNA NGS; Sarcoma

DOI: https://doi.org/10.1038/s41598-026-46618-3