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.