Fragment ligands of the m6A-RNA reader YTHDF2

TitleFragment ligands of the m6A-RNA reader YTHDF2
Publication TypeJournal Article
Year of Publication2022
AuthorsNai F., Nachawati R., Zálešák F., Wang X., Li Y., Caflisch A.
JournalACS Medicinal Chemistry Letters
Volume13
Start Page1500
Issue9
Pagination1500-1509
Date Published2022/08/17
Type of ArticleResearch Article
Abstract

We report 17 small-molecule ligands that compete with N6-methyladenosine (m6A) for binding to the m6A-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.We report 17 small-molecule ligands that compete with N6-methyladenosine (m6A) for binding to the m6A-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.

DOI10.1021/acsmedchemlett.2c00303
pubindex

0283

Alternate JournalACS Med. Chem. Lett.