In vivo safety assessment of METTL3 inhibitors STM2457 in neuroblastoma therapy

The present study investigated the therapeutic potential and safety profile of two N6-adenosine-methyltransferase 70 kDa subunit (METTL3) inhibitors, UZH1a and STM2457, in NB. A toxicity test of zebrafish showed that the maximum tolerated concentration of UZH1a and STM2457 was 20 μg/ml, and there were some toxic reactions including delayed yolk sac absorption but without notable mortality.

Furthermore, through a series of in vitro and in vivo experiments, both UZH1a and STM2457 markedly inhibited SK-N-SH cells viability, migration and invasion, while potently promoting apoptosis, and effectively inhibiting the growth and migration of zebrafish xenograft tumors. Mechanistically, molecular analysis revealed that UZH1a and STM2457 downregulated the gene expression levels of pro-tumorigenic factors (basic helix-loop-helix family member e41, SREBF chaperone, IL-6, and IL-1β) and upregulated the expression of antitumor cytokine (TNF-α).