Identification of novel 2, 6-Di-substituted Imidazo[1,2-a]pyridine derivatives as potent METTL3 inhibitors

METTL3, the core catalytic subunit of the N⁶-methyladenosine (m⁶A) methyltransferase complex, aberrantly overexpressed in various cancers and emerged as a potential target for cancer treatment. Here, we report the discovery of a series of 2, 6-di-substituted imidazo[1,2-a]pyridine derivatives as novel, potent, and selective METTL3 inhibitors. Compound 30t exhibited excellent inhibitory activity against METTL3 with an IC₅₀ value of 45.31 nM and good antiproliferation ability in ovarian cancer SKOV3 and acute myeloid leukemia MOLM-13 cells with IC₅₀ values of 6.42 μM and 12.34 μM, respectively. Compound 30t exhibited high selectivity towards METTL3 compared to DNMT1, EZH1, MLL1, and PRMT1. In addition, 30t reduced the m⁶A level of total RNA in MOLM-13 and SKOV3 cells, induced cell apoptosis, and inhibited cell migration. Western blot assay demonstrated that 30t could reduce the expression of m⁶A downstream target genes (c-MYC and BCL2). Meanwhile, compound 30t displayed good pharmacokinetic properties and favorable antitumor activity in vivo. Collectively, this study provides a novel compound for further development of anticancer drugs.