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

ChemMedChem. 2020 May 6;15(9):744-748. doi: 10.1002/cmdc.202000011. Epub 2020 Mar 23.


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.

Keywords: Docking; HTRF; METTL3/METTL14; Methyltransferase; m6A; protein crystallography.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Methyltransferases / antagonists & inhibitors*
  • Methyltransferases / metabolism
  • Models, Molecular
  • Molecular Conformation
  • Stereoisomerism


  • Enzyme Inhibitors
  • Methyltransferases
  • METTL3 protein, human