Small‐Molecule Inhibitors of METTL3, the Major Human Epitranscriptomic Writer

The RNA methylase METTL3 catalyzes the transfer of a methyl group from the cofactor S‐adenosyl‐L‐methionine (SAM) to the N 6 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.