METTL3 Inhibitors for Epitranscriptomic Modulation of Cellular Processes

Abstract

The methylase METTL3 is the writer enzyme of the N⁶ -methyladenosine (m⁶ 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 m⁶ 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., m¹ A, m⁶ A_m , m⁷ G), suggesting selectivity of the developed compound towards other RNA methyltransferases.

Keywords: METTL3; RNA methyltransferase inhibitor; epitranscriptomics; leukemia; m6A.