RESUMEN

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 Am , m7 G), suggesting selectivity of the developed compound towards other RNA methyltransferases.

Asunto(s)

Inhibidores Enzimáticos/farmacología , Metiltransferasas/antagonistas & inhibidores , ARN Interferente Pequeño/farmacología , Células CACO-2 , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Humanos , Metiltransferasas/metabolismo , Estructura Molecular , ARN Interferente Pequeño/química , Relación Estructura-Actividad