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

R.K. Bedi; D. Huang; S.A. Eberle; L. Wiedmer; P. Śledź; A. Caflisch

Journal: ChemMedChem
Year: 2020
Volume: 15
Issue: 9
Pages: 744-748
DOI: 10.1002/cmdc.202000011
Type of Publication: Journal Article

epitranscriptomics; 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.