METTL3 Inhibitors for Epitranscriptomic Modulation of Cellular Processes
Elena Moroz, Danzhi Huang, R.K. Bedi, Sherry Cheriyamkunnel, Elena Bochenkova, A. Dolbois, Maciej D. Rzeczkowski, Yaozong Li, L. Wiedmer, Amedeo Caflisch
Abstract
Abstract 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.