{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Chemistry",
    "University of Minnesota",
    "Division of Gastroenterology and Hepatology",
    "Mayo Clinic",
    "Department of Medicinal Chemistry",
    "Institute for Therapeutics Discovery and Development, College of Pharmacy",
    "Mayo Clinic Comprehensive Cancer Center",
    "Department of Biochemistry, Molecular Biology, and Biophysics"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 22,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Nora R. Vail"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Luke C. Doskey"
    },
    {
      "affs": [
        4,
        1
      ],
      "name": "Elliott J. Peterson"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Cole R. Scholtz"
    },
    {
      "affs": [
        5,
        1
      ],
      "name": "Ricardo Gallardo-Macias"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Shalil Khanal"
    },
    {
      "affs": [
        6,
        3
      ],
      "name": "Sarah A. Buhrow"
    },
    {
      "affs": [
        4,
        1
      ],
      "name": "Joseph E. McPherson"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Tomás I. Sepulveda"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Trina L. Zanon"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Sofia Jerez"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Juliana R. Alexander"
    },
    {
      "affs": [
        4,
        1,
        5
      ],
      "name": "Vadim J. Gurvich"
    },
    {
      "affs": [
        4,
        1
      ],
      "name": "Natalia Y. Tretyakova"
    },
    {
      "affs": [
        6,
        3
      ],
      "name": "Joel M. Reid"
    },
    {
      "affs": [
        7,
        1
      ],
      "name": "Ke Shi"
    },
    {
      "affs": [
        7,
        1
      ],
      "name": "Hideki Aihara"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Joseph J. Topczewski"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Harmeet Malhi"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Vijay H. Shah"
    },
    {
      "affs": [
        0,
        1,
        4
      ],
      "name": "William C.K. Pomerantz"
    },
    {
      "name": "William Charles Krause Pomerantz",
      "orcid": "0000-0002-0163-4078"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bs5e7rw5syyzp.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15009359/v1",
  "fulltext_url": null,
  "id": "bs5e7rw5syyzp",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009359/v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Protein Degradation and Inhibitors"
    ]
  ],
  "openalex": "W7214099412",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-23",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/bs5e7rw5syyzp.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:21Z",
      "native_id": "10.26434/chemrxiv.15009359",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009359/v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Protein Degradation and Inhibitors",
      "subfield": "molecular-biology"
    }
  ],
  "title": "BET Bromodomain Pan-D1-Biased Inhibitors with Improved Drug-Like Properties and hERG Profiles as Therapies for Inflammatory Liver Injury",
  "title_text": "BET Bromodomain Pan-D1-Biased Inhibitors with Improved Drug-Like Properties and hERG Profiles as Therapies for Inflammatory Liver Injury",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:21Z",
  "url": "https://research.draconitic.com/paper/bs5e7rw5syyzp",
  "venue": "ChemRxiv",
  "versions": []
}