Discovery of a Synergistic Inhibitor of cAMP-Response Element Binding Protein (CREB)-Mediated Gene Transcription with <b>666</b>-<b>15</b>

CREB is a transcription factor implicated in the pathogenesis of multiple cancers. Targeting CREB is a promising strategy to develop potential cancer therapeutics. Previously, we identified <b>666</b>-<b>15</b> as a potent CREB inhibitor. Herein, we designed an ester prodrug of <b>666</b>-<b>15</b> through a long-range <i>O</i>,<i>N</i>-acyl transfer reaction for improved aqueous solubility. Unexpectedly, we discovered a small molecule <b>11</b> (<b>653</b>-<b>47</b>) that can potentiate the CREB inhibitory activity of <b>666</b>-<b>15</b> although <b>653</b>-<b>47</b> alone does not inhibit CREB.