Premium
METTL3 Inhibitors for Epitranscriptomic Modulation of Cellular Processes
Author(s) -
MorozOmori Elena V.,
Huang Danzhi,
Kumar Bedi Rajiv,
Cheriyamkunnel Sherry J.,
Bochenkova Elena,
Dolbois Aymeric,
Rzeczkowski Maciej D.,
Li Yaozong,
Wiedmer Lars,
Caflisch Amedeo
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100291
Subject(s) - n6 methyladenosine , methyltransferase , rna , rna methylation , messenger rna , methylation , potency , enzyme , chemistry , biochemistry , biology , microbiology and biotechnology , pharmacology , in vitro , gene
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.