{
  "abstract": "Various approaches have been explored to address the on-target, off-tissue toxicity of PROTACs and molecular glues, but most fall short in achieving robust in vivo selectivity and efficacy. In this study, we introduce a delivery strategy that enables tissue-selective deployment of an ultra-potent, picomolar-active DCAF16-recruiting intramolecular bivalent glue (IBG3) for BRD4 degradation in prostate cancer models by targeting the prostate-specific membrane antigen (PSMA). We first introduced rational modifications to IBG3 to install a suitable conjugation handle for PSMA ligand attachment, and incorporated a cathepsins-sensitive cleavable linker together with a dual functional polycarboxylate linker that enhances PSMA binding while suppressing passive diffusion. Selective BRD4 degradation was validated by multiple orthogonal assays in vitro and in vivo. The lead conjugate IBG-P3 achieved 79.8% tumor growth inhibition at 0.01 mg/kg in PC3-PIP xenografts, while an epimeric control lacking PSMA binding was inactive. Importantly, robust antitumor efficacy was further confirmed in an endogenous PSMA-expressing LNCaP xenograft model, where IBG-P3 achieved 72.6% tumor growth inhibition at a dose as low as 0.001 mg/kg, significantly outperforming the parent compound IBG3. This study provides the first in vivo validation of IBG degrader and establishes a preclinical framework for PSMA-guided delivery of potent degraders.",
  "abstract_shown": true,
  "affiliations": [
    "Lachman Institute for Pharmaceutical Development, School of Pharmacy, University of Wisconsin-Madison, WI 53705, USA.",
    "Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, WI 53792, USA.",
    "Department of Radiology, University of Wisconsin School of Medicine and Public Health, WI 53792, USA.",
    "Carbone Cancer Center, University of Wisconsin-Madison, WI 53792, USA.",
    "Department of Chemistry, University of Wisconsin-Madison, WI 53706, USA."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Deqin Cai"
    },
    {
      "affs": [
        0
      ],
      "name": "Chunrong Li"
    },
    {
      "affs": [
        1
      ],
      "name": "Malick Bio Idrissou"
    },
    {
      "affs": [
        0
      ],
      "name": "Nina J Hawkins"
    },
    {
      "affs": [
        0
      ],
      "name": "Ramesh Mudududdla"
    },
    {
      "affs": [
        0
      ],
      "name": "Xuankun Chen"
    },
    {
      "affs": [
        0
      ],
      "name": "Thao-Vy T Nguyen"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiaolei Li"
    },
    {
      "affs": [
        1,
        2,
        3
      ],
      "name": "Reinier Hernandez"
    },
    {
      "affs": [
        0,
        3,
        4
      ],
      "name": "Weiping Tang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8ptmpxv5y2p1j.bib",
  "cited_by": 0,
  "doi": "10.1016/j.apsb.2026.08.008",
  "fulltext_url": "https://europepmc.org/articles/PMC13712433",
  "id": "8ptmpxv5y2p1j",
  "issns": [
    "2211-3835",
    "2211-3843"
  ],
  "landing_url": "https://europepmc.org/article/MED/42948766",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Original Article"
    ],
    [
      "openalex",
      "1312|Protein Degradation and Inhibitors"
    ]
  ],
  "openalex": "W7202182853",
  "pdf_url": "https://europepmc.org/articles/PMC13712433?pdf=render",
  "pmcid": "PMC13712433",
  "pmid": "42948766",
  "published": "2026-08-11",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/8ptmpxv5y2p1j.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T00:20:35Z",
      "native_id": "MED:42948766",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42948766"
    },
    {
      "first_seen": "2026-10-31T12:23:00Z",
      "native_id": "PMC13712433",
      "source": "pmc",
      "url": "https://doi.org/10.1016/j.apsb.2026.08.008"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Protein Degradation and Inhibitors",
      "subfield": "molecular-biology"
    }
  ],
  "title": "In vivo validation of intramolecular bivalent glues targeting PSMA reveals potent and tissue-selective BRD4 degradation in prostate cancer.",
  "title_text": "In vivo validation of intramolecular bivalent glues targeting PSMA reveals potent and tissue-selective BRD4 degradation in prostate cancer.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:23:00Z",
  "url": "https://research.draconitic.com/paper/8ptmpxv5y2p1j",
  "venue": "Acta pharmaceutica Sinica. B",
  "versions": []
}