Fragment Ligands of the m⁶A‑RNA Reader YTHDF2

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.