{
  "abstract": "Cys2-His2 (C2H2) zinc finger (ZF)-containing proteins are the largest family of human DNA-binding transcription factors (TFs), a class of proteins that has long been considered undruggable. Significant progress has recently been made in the development of immunomodulatory imide drugs (IMiDs) that induce the degradation of proteins that possess the G-loop CXXCG degron, including these transcription factors. Despite these advances, the identification of IMiD-based molecular glues that selectively induce the degradation of a single protein, and the rational design of such compounds, remains challenging. Here we report the serendipitous discovery that 5-tBu-thalidomide (tBu-Thal, 5) potently and selectively induces proteasomal degradation of a single C2H2 ZF-containing TF, FLT3 interacting zinc finger 1 (FIZ1), in six cell lines. While FIZ1 contains 11 C2H2 ZFs, six of which contain the G-loop CXXCG degron necessary for IMiD-induced degradation, we demonstrate that this degradation is mediated exclusively by ZF8. Computational modeling of the CRL4CRBN-IMiD-FIZ1 complex enabled rationalization of why tBu-Thal (5) selectively engages with ZF8, and hints at a strategy for more rational design of selective IMiD-based degraders. tBu-Thal (5) was employed in ChIP-seq studies to identify a motif matching the CRX binding site, consistent with prior reports. We also identified enriched motifs resembling binding sites of the transcription factors ZBTB32 and ARID3a, which have not previously been associated with FIZ1. IP-MS studies indicated that FIZ1 associates with C1QBP and YBX1. C1QBP is involved in DNA damage repair, suggesting a role for FIZ1 in this process. These data show that tBu-Thal (5) is a powerful molecular tool to selectively dissect the role of FIZ1 in complex biological settings.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Chemistry & Biochemistry, University of California Los Angeles, Los Angeles, California90095, United States.",
    "Department of Chemistry, Chemistry Research Laboratory, University of Oxford, OxfordOX1 3TA, U.K.",
    "Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York10065, United States.",
    "Tri-Institutional PhD Program of Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York10065, United States.",
    "Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York10065, United States.",
    "Department of Chemistry, Gebze Technical University, Kocaeli41400, Türkiye.",
    "Department of Statistics, University of Oxford, OxfordOX1 3LB, U.K.",
    "California Nano Systems Institute, University of California Los Angeles, Los Angeles, California90095, United States.",
    "Molecular Biology Institute, University of California Los Angeles, Los Angeles, California90095, United States.",
    "GSK, Medicines Research Centre, StevenageSG1 2NY, U.K.",
    "Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California90095, United States."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Patrick J Brennan",
      "orcid": "0009-0008-8737-9370"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Ruiyang Guo"
    },
    {
      "affs": [
        4
      ],
      "name": "Alban Ordureau",
      "orcid": "0000-0002-4924-8520"
    },
    {
      "affs": [
        0
      ],
      "name": "Sarah E Singleton",
      "orcid": "0009-0001-6615-8906"
    },
    {
      "affs": [
        0
      ],
      "name": "Miranda Li"
    },
    {
      "affs": [
        0,
        5
      ],
      "name": "Fatma Albayrak"
    },
    {
      "affs": [
        0
      ],
      "name": "Connor H Chang"
    },
    {
      "affs": [
        0
      ],
      "name": "Lorena Yu Liao",
      "orcid": "0009-0008-0608-6518"
    },
    {
      "affs": [
        6
      ],
      "name": "Charlotte M Deane",
      "orcid": "0000-0003-1388-2252"
    },
    {
      "affs": [
        0,
        7,
        8
      ],
      "name": "Kendall N Houk",
      "orcid": "0000-0002-8387-5261"
    },
    {
      "affs": [
        9
      ],
      "name": "Michael M Hann",
      "orcid": "0000-0003-4360-9505"
    },
    {
      "affs": [
        9
      ],
      "name": "Lewis L Brayshaw"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Heeseon An",
      "orcid": "0000-0002-8518-4077"
    },
    {
      "affs": [
        0,
        1,
        7,
        8,
        10
      ],
      "name": "Stuart J Conway",
      "orcid": "0000-0002-5148-117X"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/527shh8rmztfz.bib",
  "cited_by": 0,
  "doi": "10.1021/jacs.6c14185",
  "fulltext_url": "https://europepmc.org/articles/PMC13587684",
  "id": "527shh8rmztfz",
  "issns": [
    "0002-7863",
    "1520-5126"
  ],
  "landing_url": "https://europepmc.org/article/MED/42915536",
  "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": [
    [
      "openalex",
      "1312|Protein Degradation and Inhibitors"
    ]
  ],
  "openalex": "W7207632029",
  "pdf_url": "https://europepmc.org/articles/PMC13587684?pdf=render",
  "pmcid": "PMC13587684",
  "pmid": "42915536",
  "published": "2026-09-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/527shh8rmztfz.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:21:02Z",
      "native_id": "MED:42915536",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42915536"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Protein Degradation and Inhibitors",
      "subfield": "molecular-biology"
    }
  ],
  "title": "5-tBu-Thalidomide Is a Selective Molecular Glue Degrader of the Transcription Factor FLT3 Interacting Zinc Finger 1 (FIZ1).",
  "title_text": "5-tBu-Thalidomide Is a Selective Molecular Glue Degrader of the Transcription Factor FLT3 Interacting Zinc Finger 1 (FIZ1).",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:21:02Z",
  "url": "https://research.draconitic.com/paper/527shh8rmztfz",
  "venue": "Journal of the American Chemical Society",
  "versions": []
}