BET Bromodomain Pan-D1-Biased Inhibitors with Improved Drug-Like Properties and hERG Profiles as Therapies for Inflammatory Liver Injury
8 affiliations
- 1Department of Chemistry
- 2University of Minnesota
- 3Division of Gastroenterology and Hepatology
- 4Mayo Clinic
- 5Department of Medicinal Chemistry
- 6Institute for Therapeutics Discovery and Development, College of Pharmacy
- 7Mayo Clinic Comprehensive Cancer Center
- 8Department of Biochemistry, Molecular Biology, and Biophysics
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.
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BibTeX
@misc{vail2026bromodomain,
title = {{BET Bromodomain Pan-D1-Biased Inhibitors with Improved Drug-Like Properties and hERG Profiles as Therapies for Inflammatory Liver Injury}},
author = {Nora R. Vail and Luke C. Doskey and Elliott J. Peterson and Cole R. Scholtz and Ricardo Gallardo-Macias and Shalil Khanal and Sarah A. Buhrow and Joseph E. McPherson and Tomás I. Sepulveda and Trina L. Zanon and Sofia Jerez and Juliana R. Alexander and Vadim J. Gurvich and Natalia Y. Tretyakova and Joel M. Reid and Ke Shi and Hideki Aihara and Joseph J. Topczewski and Harmeet Malhi and Vijay H. Shah and William C.K. Pomerantz and William Charles Krause Pomerantz},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15009359/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009359/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - BET Bromodomain Pan-D1-Biased Inhibitors with Improved Drug-Like Properties and hERG Profiles as Therapies for Inflammatory Liver Injury
AU - Nora R. Vail
AU - Luke C. Doskey
AU - Elliott J. Peterson
AU - Cole R. Scholtz
AU - Ricardo Gallardo-Macias
AU - Shalil Khanal
AU - Sarah A. Buhrow
AU - Joseph E. McPherson
AU - Tomás I. Sepulveda
AU - Trina L. Zanon
AU - Sofia Jerez
AU - Juliana R. Alexander
AU - Vadim J. Gurvich
AU - Natalia Y. Tretyakova
AU - Joel M. Reid
AU - Ke Shi
AU - Hideki Aihara
AU - Joseph J. Topczewski
AU - Harmeet Malhi
AU - Vijay H. Shah
AU - William C.K. Pomerantz
AU - William Charles Krause Pomerantz
PY - 2026
DA - 2026/09/23
PB - ChemRxiv
DO - 10.26434/chemrxiv.15009359/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009359/v1
AB - 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.
ER -