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

• Published in: ChemMedChem Vol. 15; no. 9; pp. 744 - 748
• Main Authors: Bedi, Rajiv K., Huang, Danzhi, Eberle, Stefanie A., Wiedmer, Lars, Śledź, Pawel, Caflisch, Amedeo
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 06.05.2020
• Subjects: Adenine; Adenosine; Crystallography; Crystallography, X-Ray; Derivatives; Docking; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; HTRF; Humans; Inhibitors; m6A; Methionine; Methylase; Methyltransferase; Methyltransferases - antagonists & inhibitors; Methyltransferases - metabolism; METTL3/METTL14; Models, Molecular; Molecular Conformation; protein crystallography; Ribonucleic acid; RNA; Stereoisomerism; METTL3/METTL14; protein crystallography; Docking; m6A; HTRF; Methyltransferase
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202000011

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. On your METTL: High‐throughput docking into the SAM‐binding site and protein X‐ray crystallography have allowed us to identify and characterize the first small‐molecule inhibitors of METTL3, the key human epitranscriptomic writer. Two compounds showed good ligand efficiency, and we propose a route for their development into potent, selective METTL3 inhibitors.