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The methylase METTL3 is the writer enzyme of the N 6 ‐methyladenosine (m 6 A) modification of RNA. Using a structure‐based drug discovery approach, we identified a METTL3 inhibitor with potency in a biochemical assay of 280 nM, while its enantiomer is 100 times less active. We observed a dose‐dependent reduction in the m 6 A methylation level of mRNA in several cell lines treated with the inhibitor already after 16 h of treatment, which lasted for at least 6 days. Importantly, the prolonged incubation (up to 6 days) with the METTL3 inhibitor did not alter levels of other RNA modifications ( i. e ., m 1 A, m 6 A m , m 7 G), suggesting selectivity of the developed compound towards other RNA methyltransferases.

METTL3 Inhibitors for Epitranscriptomic Modulation of Cellular Processes