Discovery of Novel Class of METTL3 Inhibitors with a Pyridin-2(1H)‑one Moiety

N ⁶-Methyladenosine methylation (m⁶A) is the most common type of RNA modification and is catalyzed primarily by the METTL3-METTL14 methyltransferase complex. METTL3 is considered a promising target for the treatment of acute myeloid leukemia (AML). However, only a few METTL3 inhibitors targeting the catalytic activity have been developed recently. Herein we report a series of novel METTL3 inhibitors bearing a pyridin-2-(1H)-one moiety by structure-based drug design. Among these, compound 15 exhibits potent inhibitory activity against METTL3 (IC₅₀ = 50 nM). Compound 15 shows moderate metabolic stability in mouse and human liver microsomes. Meanwhile, in MV411 and SKM1 cell lines, compound 15 is able to potently inhibit cell proliferation. These results make compound 15 a promising lead compound for further optimization.