{
  "abstract": "Heterobifunctional compounds (HBCs) that facilitate target protein degradation (TPD) by recruiting an E3 ligase complex have emerged as therapeutic options for cancer. Current screening approaches often prioritize protein degradation over anticancer activity, potentially missing therapeutically relevant compounds. To address this, we developed a viability-based screening strategy using isogenic wild-type, MAP3K1-knockout, and CRBN-knockout cell lines to identify HBCs with target- and E3-ligase-dependent anticancer effects. This approach identified HBC-8, which is > 30-fold more potent than the parent MAP3K1 inhibitor and induces S-phase arrest, growth inhibition, and apoptosis in a MAP3K1- and CRBN-dependent manner. HBC-8 degrades MAP3K1; however, proteome-wide, genome-wide, and large-scale viability-based screens indicate that the anticancer activity of HBC-8 also relies on the disruption of the ubiquitin-proteasome system and protein translation machinery, extending beyond MAP3K1 degradation alone. Target dependence of HBC-8 was established using a large-scale viability screen in 869 cancer cell lines, and the anticancer effects correlated with the expression levels of the target (MAP3K1) and E3 ligase (CRBN). Furthermore, HBC-8 showed antitumor effects in an in vivo orthotopic ovarian cancer model without observable toxicity, supporting the use of isogenic cell lines for chemical genetic screens as a rapid, holistic approach to identify therapeutically relevant HBCs that also degrade the target protein.",
  "abstract_shown": true,
  "affiliations": [
    "Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45267, USA.",
    "Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, 68198, USA.",
    "Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA.",
    "Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA.",
    "Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.",
    "The ChemoGenix CRISPR Screening Platform of the Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, QC, H3T 1J4, Canada.",
    "Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45267, USA. nataraah@ucmail.uc.edu.",
    "Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, 68198, USA. nataraah@ucmail.uc.edu.",
    "Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA. nataraah@ucmail.uc.edu.",
    "Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA. nataraah@ucmail.uc.edu."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 30,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Lelisse T Umeta"
    },
    {
      "affs": [
        1
      ],
      "name": "Jayapal Reddy Mallareddy"
    },
    {
      "affs": [
        1
      ],
      "name": "Sarbjit Singh"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Karan Vishwakarma"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Smitha Kizhake"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Wangbin Wu"
    },
    {
      "affs": [
        1
      ],
      "name": "Amritha G Kizhake"
    },
    {
      "affs": [
        1
      ],
      "name": "Lidia Boghean"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Suchita Vishwakarma"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Mihir Kachhia"
    },
    {
      "affs": [
        1
      ],
      "name": "A J Sallee"
    },
    {
      "affs": [
        3
      ],
      "name": "Vaishnavi Sunil Joshi"
    },
    {
      "affs": [
        1
      ],
      "name": "Katelyn L O'Neill"
    },
    {
      "affs": [
        1
      ],
      "name": "Lisa Humphrey-Brattain"
    },
    {
      "affs": [
        3
      ],
      "name": "Linda Chee"
    },
    {
      "affs": [
        4
      ],
      "name": "Matthew G Rees"
    },
    {
      "affs": [
        4
      ],
      "name": "Melissa M Ronan"
    },
    {
      "affs": [
        4
      ],
      "name": "Jennifer A Roth"
    },
    {
      "affs": [
        5
      ],
      "name": "Andrew Chatr-Aryamontri"
    },
    {
      "affs": [
        5
      ],
      "name": "Thierry Bertomeu"
    },
    {
      "affs": [
        1
      ],
      "name": "Kabhilan Mohan"
    },
    {
      "affs": [
        1
      ],
      "name": "Yuanhong Chen"
    },
    {
      "affs": [
        3
      ],
      "name": "Kyle Hewitt"
    },
    {
      "affs": [
        1
      ],
      "name": "Grinu Mathew"
    },
    {
      "affs": [
        1
      ],
      "name": "Adrian Black"
    },
    {
      "affs": [
        3
      ],
      "name": "Gargi Ghosal"
    },
    {
      "affs": [
        1
      ],
      "name": "Xu Luo"
    },
    {
      "affs": [
        1
      ],
      "name": "Jixin Dong"
    },
    {
      "affs": [
        1
      ],
      "name": "Nicholas T Woods"
    },
    {
      "affs": [
        6,
        7,
        8,
        9
      ],
      "name": "Amarnath Natarajan",
      "orcid": "0000-0001-5067-0203"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0b2e51v2d5bwq.bib",
  "cited_by": 0,
  "doi": "10.1186/s43556-026-00632-z",
  "fulltext_url": "https://europepmc.org/articles/PMC13719937",
  "id": "0b2e51v2d5bwq",
  "issns": [
    "2662-8651"
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  "landing_url": "https://europepmc.org/article/MED/42955492",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
    ],
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      "openalex",
      "1312|Protein Degradation and Inhibitors"
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  "openalex": "W7224157737",
  "pdf_url": "https://europepmc.org/articles/PMC13719937?pdf=render",
  "pmcid": "PMC13719937",
  "pmid": "42955492",
  "published": "2026-10-28",
  "publisher": "Springer",
  "ris": "https://research.draconitic.com/paper/0b2e51v2d5bwq.ris",
  "sources": [
    {
      "first_seen": "2026-11-01T00:20:36Z",
      "native_id": "MED:42955492",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42955492"
    },
    {
      "first_seen": "2026-11-02T12:23:48Z",
      "native_id": "PMC13719937",
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      "url": "https://doi.org/10.1186/s43556-026-00632-z"
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Protein Degradation and Inhibitors",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Chemical genetic screens combine target dependence with efficacy: discovery of a MAP3K1 degrader (HBC-8) with anticancer activities.",
  "title_text": "Chemical genetic screens combine target dependence with efficacy: discovery of a MAP3K1 degrader (HBC-8) with anticancer activities.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T12:20:54Z",
  "url": "https://research.draconitic.com/paper/0b2e51v2d5bwq",
  "venue": "Molecular biomedicine",
  "versions": []
}