Development of BET inhibitors as potential treatments for cancer: A new carboline chemotype.

Abstract We describe our efforts to introduce structural diversity to a previously described triazole-containing N1-carboline series of bromodomain and extra-terminal (BET) inhibitors. N9 carbolines were designed to retain favorable binding interactions that the N1-carbolines possess. A convergent synthetic route enabled modifications to reduce clearance, enhance physicochemical properties, and improve the overall in vitro profile. This work led to the identification of a potent BET inhibitor, (S)-2‐{8‐fluoro‐5‐[(3‐fluoropyridin‐2‐yl)(oxan‐4‐yl)methyl]‐7‐[4‐(2H3)methyl‐1‐methyl‐1H‐1,2,3‐triazol‐5‐yl]‐5H‐pyrido[3,2‐b]indol‐3‐yl}propan‐2‐ol (10), a compound with enhanced oral exposure in mice. Subsequent evaluation in a mouse triple-negative breast cancer tumor model revealed efficacy at 4 mg/kg of N9-carboline 10.