Rational design and development of selective BRD7 bromodomain inhibitors and their activity in prostate cancer

Abstract

Bromodomain-containing proteins are readers of acetylated lysine and play important roles in cancer. Bromo-domain-containing protein 7 (BRD7) has been implicated in multiple malignancies; however, there are no selective chemical probes to study its function in disease. Using crystal structures of BRD7 and BRD9 bromodomains (BDs) bound to BRD9-selective ligands, we identified a binding pocket exclusive to BRD7. We synthesized a se-ries of ligands designed to occupy this binding region and identified two BRD7-selective inhibitors, 1-78 and 2-77, that bind with nanomolar affinity to the BRD7 BD. Our binding mode analyses indicate that these ligands oc-cupy a uniquely accessible binding cleft in BRD7 and maintain key interactions with the asparagine and tyrosine residues critical for acetylated lysine binding. Finally, we validated the utility and selectivity of the compounds in cell-based models of prostate cancer.