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Small-Molecule Inhibitors of METTL3, the Major Human Epitranscriptomic Writer |
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| Authors: | Rajiv K. Bedi Dr. Danzhi Huang Stefanie A. Eberle Dr. Lars Wiedmer Dr. Pawel Śledź Prof. Amedeo Caflisch |
| Affiliation: | 1. Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland;2. Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland Current address: Department of Biomedical Sciences Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark |
| Abstract: | 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: | Methyltransferase m6A Docking protein crystallography HTRF METTL3/METTL14 |