6-Methylquinazolin-4(3H)-one Based Compounds as BRD9 Epigenetic Reader Binders: A Rational Combination of in silico Studies and Chemical Synthesis

6-methylquinazolin-4(3H)-one-based compounds were here identified and synthesized as novel binders ofbromodomain-containing protein 9(BRD9)epigenetic reader.Accounting a fast and efficient synthetic route aimed to easily obtain differently 2-and 8-disubstituted 6-methylquinazolin-4(3H)-onederivatives, a virtual library of synthesizable items was built and submitted to molecular docking experiments.Based on two 3D structure-based pharmacophore modelsrecently developed by us on BRD9, 16 compounds were selectedandsynthesized, using mild conditions with good yields in relatively short reaction times. Among them, 14, 16, 18, 22,and 26emerged as the most potent compounds of these series, able to bind BRD9at low micromolar range concentrations.These molecules also showed a promisingselective behaviour when tested against BRD4bromodomain. These results highlighted the quinazolin-4(3H)-one chemical core as a valuable scaffold for developing promising BRD9 binders