Highly selective, small-molecule inhibitors of PRC2. (A) Scaffold demonstrating that several of the recently developed EZH2 or EZH2/1 inhibitors all possess a pyridone motif as well as an indole or indazole core. The inserted table details the identity of each designated substituent of the described inhibitors. (B) Chemical structure of EPZ-6438. (C) Chemical structure of Constellation Pharmaceuticals compound 3, the first non–pyridone-containing EZH2 inhibitor.