Discovery of Novel Class of METTL3 Inhibitors with a Pyridin-2(1 <i>H</i> )-one Moiety

<i>N</i> 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-(1<i>H</i>)-one moiety by structure-based drug design. Among these, compound <b>15</b> exhibits potent inhibitory activity against METTL3 (IC₅₀ = 50 nM). Compound <b>15</b> shows moderate metabolic stability in mouse and human liver microsomes. Meanwhile, in MV411 and SKM1 cell lines, compound <b>15</b> is able to potently inhibit cell proliferation. These results make compound <b>15</b> a promising lead compound for further optimization.