Small-molecule inhibitors of METTL3, the major human epitranscriptomic writer

TitleSmall-molecule inhibitors of METTL3, the major human epitranscriptomic writer
Publication TypeJournal Article
Year of Publication2020
AuthorsBedi R.K, Huang D., Eberle S.A, Wiedmer L., Śledź P., Caflisch A.
Date Published2020 Mar 11
Type of ArticleResearch Article
Keywordsepitranscriptomics, m6A writer, small molecule binding, Virtual Screening, X-ray crystallography

The RNA methylase METTL3 catalyzes the transfer of a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to the N6 atom of adenine. We have screened a library of 4000 analogues and derivatives of the adenosine moiety of SAM by high-throughput docking into METTL3. Two series of adenine derivatives were identified in silico, and the binding mode of six of the predicted inhibitors was validated by protein crystallography. Two compounds, one for each series, show good ligand efficiency. We propose a route for their further development into potent and selective inhibitors of METTL3.



Alternate JournalChemMedChem
PubMed ID32159918
Highlight Role: 
Drug Design