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

CREB is a transcription factor involved in the development of various cancers, making it a promising target for cancer therapy. We previously identified 666-15 as a potent small-molecule inhibitor of CREB. In this study, we developed an ester prodrug of 666-15 via a long-range O,N-acyl transfer reaction to enhance its aqueous solubility.

Unexpectedly, we also identified a small molecule, compound 11 (653-47), that significantly enhances the CREB inhibitory activity of 666-15, despite having no intrinsic CREB inhibitory 666-15 inhibitor effect when used alone.