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METTL3 inhibitors for epitranscriptomic modulation of cellular processes

Authors:
E.V. Moroz-Omori; D. Huang; R.K. Bedi; S.J. Cheriyamkunnel; E. Bochenkova; A. Dolbois; M.D. Rzeczkowski; Y. Li; L. Wiedmer; A. Caflisch

Journal: ChemMedChem
Year: 2021
Volume: 16
Issue: 19
Pages: 3035-3043
DOI: 10.1002/cmdc.202100291
Type of Publication: Journal Article

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. , m1A, m 6 A m , m 7 G), suggesting selectivity of the developed compound towards other RNA methyltransferases.