@article{bibcite_673,
  author = {A. Invernizzi and F. Nai and R. K. Bedi and P. A. Vargas-Rosales and Y. Li and E. Bochenkova and M. Herok and F. Z{\'a}le{\v s}{\'a}k and A. Caflisch},
  title = {Discovery of YTHDF2 Ligands by Fragment-Based Design},
  abstract = {<p>N6-Adenosine methylation is the most abundant modification of mRNA. The three members of the YTH domain family proteins (YTHDF1-3) recognize in the cytoplasm the m6A-RNA modification. We carried out a screening campaign by fragment-based high-throughput docking into YTHDF2 that resulted in the identification of six ligands with a hit rate of 13\%. The acquisition of 28 analogues of the docking hits provided an additional set of 10 active compounds (IC50 < 100 {\textmu}M). Further optimization of a ligand-efficient fragment by the synthesis of 32 derivatives culminated in a series of YTHDF2 ligands which show low-micromolar affinity measured by a fluorescence-polarization (FP) assay and a homo-geneous time-resolved fluorescence-based (HTRF) assay. The series is characterized by very favorable ligand efficiency (of about 0.3 {\textendash} 0.4 kcal/mol per non-hydrogen atom). Compound 23 binds to YTHDF2 according to the FP and HTRF assays with IC50 values of 2 {\textmu}M and 10 {\textmu}M, respectively, and it is selective against all the other YTH reader proteins. Sev-eral compounds of the series bind to the three YTHDF proteins with similar low-micromolar affinity, while they are less potent for YTHDC1 and YTHDC2. In contrast, compounds 17 and 30 bind also to YTHDC2, with affinity of 9 {\textmu}M and 7 {\textmu}M, respectively. We also disclose six crystal structures of YTHDF2 in the complex with the fragments identified by docking.</p>},
  year = {2025},
  journal = {ACS Bio \& Med Chem Au},
  volume = {5},
  pages = {753{\textendash}765},
  month = {2025 Jun 27},
  url = {https://pubs.acs.org/doi/full/10.1021/acsbiomedchemau.5c00099},
  doi = {10.1021/acsbiomedchemau.5c00099},
  language = {eng},
}