Development of BET Inhibitors as Potential Treatments for Cancer: Optimization of Pharmacokinetic Properties

Abstract

We describe the synthesis of triazole-containing carboline derivatives and their utility as bromodomain and extra-terminal (BET) inhibitors. A convergent synthetic route permitted the detailed investigation of deuteration and fluorination strategies to reduce clearance while maintaining a favorable <i>in vitro</i> profile. This work led to the identification of a potent BET inhibitor, 2-{8-fluoro-3-[4-(²H₃)methyl-1-methyl-1<i>H</i>-1,2,3-triazol-5-yl]-5-[(<i>S</i>)-(oxan-4-yl)(phenyl)methyl]-5<i>H</i>-pyrido[3,2-<i>b</i>]indol-7-yl}propan-2-ol (<b>15</b>), which demonstrated reduced clearance and an improved pharmacokinetic (PK) profile across preclinical species. Importantly, no major metabolite was observed when <b>15</b> was incubated with human hepatocytes (hHEP) for 2 h. This study culminated with the evaluation of <b>15</b> in a mouse triple-negative breast cancer (TNBC) tumor model where it demonstrated robust efficacy at low doses.