BET Bromodomain Pan-D1-Biased Inhibitors with Improved Drug-Like Properties and hERG Profiles as Therapies for Inflammatory Liver Injury
Year: 2026
Type: preprint
Abstract: 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.
Source: ChemRxiv
Authors: Nora R. Vail, Luke C. Doskey, Elliott J. Peterson, Cole R. Scholtz, Ricardo Gallardo-Macias, Shalil Khanal, Sarah A. Buhrow, Joseph E. McPherson, Tomás I. Sepulveda, Trina L. Zanon, Sofia Jerez, Juliana R. Alexander, Vadim J. Gurvich, Natalia Y. Tretyakova, Joel M. Reid, Ke Shi, Hideki Aihara, Joseph J. Topczewski, Harmeet Malhi, Vijay H. Shah, William C.K. Pomerantz, William Charles Krause Pomerantz
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7214099412