Fragment Ligands of the m(6)A-RNA Reader YTHDF2

[Image: see text] We report 17 small-molecule ligands that compete with N6-methyladenosine (m(6)A) for binding to the m(6)A-reader domain of YTHDF2 (YT521-B homology domain family 2). We determined their binding mode at high resolution by X-ray crystallography and quantified their affinity by a fluo...

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Detalles Bibliográficos
Autores principales: Nai, Francesco, Nachawati, Raed, Zálešák, František, Wang, Xiang, Li, Yaozong, Caflisch, Amedeo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9466600/
https://www.ncbi.nlm.nih.gov/pubmed/36110386
http://dx.doi.org/10.1021/acsmedchemlett.2c00303
Descripción
Sumario:[Image: see text] We report 17 small-molecule ligands that compete with N6-methyladenosine (m(6)A) for binding to the m(6)A-reader domain of YTHDF2 (YT521-B homology domain family 2). We determined their binding mode at high resolution by X-ray crystallography and quantified their affinity by a fluorescence-based binding assay. 6-Cyclopropyluracil and a pyrazolopyrimidine derivative have favorable ligand efficiencies of 0.47 and 0.38 kcal mol(–1) per non-hydrogen atom, respectively. They represent useful starting points for hit optimization.

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