Citations 1
BET Bromodomain Pan-D1-Biased Inhibitors with Improved Drug-Like Properties and hERG Profiles as Therapies for Inflammatory Liver Injury
Vail, Nora R. , Doskey, Luke C. , Peterson, Elliott , Scholtz, Cole R. , Gallardo‐Macias, Ricardo , Khanal, Shalil , Buhrow, Sarah A. , McPherson, Joseph E., Sepulveda, Tomás I., Zanon, Trina L., Jerez, Sofia, Alexander, Juliana R. , Gurvich, Vadim J. , Reid, Joel M. , Shi, Ke , Aihara, Hideki , Topczewski, Joseph J., Malhi, Harmeet , Shah, Vijay H. , Pomerantz, William C. K. , Tretyakova, Natalia Y. , Shi, Ke, Topczewski, Joseph J.
No container title available | September 23, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
BET bromodomain inhibitors are efficacious as anti-inflammatory compounds, but clinical translation is hampered by dose-limiting toxicities from non-selective inhibition. We herein report compounds 16 and 26, based on previously reported 4-methyl-1,2,3-triazole-based inhibitor, DW34. 16 has a BRD4 BD1 Ki of 10 nM, and up to 13–38-fold selectivity for BRD4 BD1 over other BD2 domains, and an improved hERG affinity of 4.24 µM over DW34. 26, A biscyclopropyl analog of 16 showed further enhancement of BD1 selectivity over BD2 (26–203-fold), but exhibited more potent hERG inhibition. Compound 16 had improved liver and plasma clearance over DW34, with good biodistribution to the liver, and had an intracellular target-engagement affinity Ki of 92 nM, with reduction of Ccl2, Cxcl1, AST, and ALT in in vitro and in vivo mouse models of liver inflammation. 16 represents a useful lead for treating inflammatory liver diseases, with improved specificity, drug-like properties, and reduced hERG affinity.