Pre-clinical anti-tumor activity and preliminary safety of METTL3 inhibitors STM2457 and UZH1a in neuroblastoma.
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BACKGROUND: Neuroblastoma (NB) is one of the most common malignant tumors in children, characterized by high heterogeneity and poor prognosis, posing notable therapeutic challenges. The objective of the present study was to investigate the therapeutic potential and safety profile of two N6-adenosine-methyltransferase 70 kDa subunit (METTL3) inhibitors, STM2457 and UZH1a, in NB. METHODS: In this study, we utilized the SK-N-SH cells and wild-type AB strain zebrafish to investigate the anti-tumor efficacy of STM2457 and UZH1a in NB. Cell counting kit-8 (CCK-8), Transwell assays, apoptosis detection, and global N6-methyladenosine (m6A) quantification were performed following 24 h exposure of STM2457 or UZH1a in SK-N-SH cells. For zebrafish, acute-toxicity screening, hepatic enzyme measurement, and xenograft establishment were conducted. Total RNA from larvae was subjected to reverse transcription quantitative polymerase chain reaction for immune-regulatory genes and transcriptome sequencing to identify key pathways. RESULTS: In vitro, both compounds showed their half-maximal inhibitory concentration (IC50) values (8.27 and 10.01 µM, respectively) and reduced global m6A levels. Functionally, STM2457 and UZH1a markedly inhibited SK-N-SH cells viability, migration, and invasion, while increasing apoptosis. In vivo, 15 µg/mL STM2457 and UZH1a effectively inhibiting the growth and migration of zebrafish xenograft tumors, and no mortality or hepatic toxicity [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] was observed. The maximum tolerated concentration was 20 µg/mL. Mechanistically, molecular analysis revealed that STM2457 and UZH1a downregulated the gene expression levels of pro-tumorigenic factors and upregulated the expression of anti-tumor cytokines. Transcriptomic sequencing results further indicated that the neuroactive ligand-receptor interaction is a key pathway through which STM2457 affected NB development. CONCLUSIONS: STM2457 and UZH1a exhibited potent anti-NB activity both in vitro and in vivo by inhibiting viability, migration, invasion, and promoting apoptosis. These findings provide a notable theoretical basis for the potential use of METTL3 inhibitors as therapeutic agents against NB.