molecules of the month

The Novartis BET bromodomain inhibitor, NVS-BET-1, is a new chemotype of BRD4 (BD1 and BD2) inhibitor. While we recently highlighted a few high-profile, selective bromodomain inhibitors from AbbVie and GSK, the Novartis team took a different approach to reaching their molecules. The Novartis team was looking for mechanisms that influence keratinocyte differentiation to treat wound healing, and identified BET inhibitors in a phenotypic screen. Interestingly, their proprietary matter emerged from a BRD4 biochemical screen that identified a totally unrelated p53-MDM2 inhibitor as a moderately potent hit. Optimization led to NVS-BET-1 which potently influences wound healing when administered orally at doses as low as 1 mg/kg. The wound-healing effects however, were lost at higher concentrations, recapitulating the “bell-shaped” dose-response curves from…