Design, synthesis, and biological evaluation of 2, 6-di-substituted indole derivatives as METTL3 inhibitors.

METTL3 (Methyltransferase Like 3) has garnered significant attention in recent years due to its pivotal role in RNA methylation modification, emerging as a novel and highly promising therapeutic target for the treatment of cancer. Here, we report the optimization and evaluation of 2, 6-di-substituted indole derivatives as METTL3 inhibitors. The representative compound 16e showed an IC50 value of 0.49 ± 0.30 nM against METTL3. Molecular dynamics simulation confirmed that the binding of 16e to METTL3. In vitro assays, 16e significantly reduced m6A levels in acute myeloid leukemia MOLM-13 cells and ovarian cancer SKOV3 cells, markedly inhibited cell proliferation, induced cells apoptosis, suppressed cells migration, and downregulated the expression of m6A downstream target genes c-MYC and BCL2. Additionally, compound 16e showed favorable pharmacokinetic characteristics and good antitumor efficacy in a SKOV3 xenograft model. Collectively, this study provides a promising candidate compound for the development of new therapeutics for cancer treatment.