{
  "abstract": "MDM2 is an oncogenic E3 ubiquitin ligase best known for targeting the tumor suppressor p53 and is frequently amplified in human cancers, including dedifferentiated liposarcoma (DDLPS). We show that supraphysiological MDM2 expression can be exploited to reprogram its ligase activity toward selective degradation of oncogenic transcriptional machinery. Using a substrate substitution strategy, we developed an MDM2-recruiting degrader dCDK9-010 that targets positive transcription elongation factor b, inducing its proteasomal degradation while simultaneously stabilizing p53. This dual action disrupts RNA polymerase II abundance and elongation, preferentially impairing enhancer-driven transcriptional programs that sustain tumor growth. In DDLPS models, this approach produces potent antitumor activity with favorable pharmacokinetic and safety profiles, triggers apoptosis, and enhances macrophage-mediated tumor cell clearance. These findings establish substrate substitution-based reprogramming of MDM2 as a generalizable targeted protein degradation strategy and identify MDM2 amplification as a predictive biomarker for therapeutic response across cancer types, with particular relevance to liposarcoma.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Surgical Oncology, and Pediatric Cancer Research Center, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Children and Adolescents' Health and Diseases, Hangzhou, China. chenyephd@zju.edu.cn.",
    "Cancer Center, Zhejiang University, Hangzhou, China. chenyephd@zju.edu.cn.",
    "Department of Surgical Oncology, and Pediatric Cancer Research Center, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Children and Adolescents' Health and Diseases, Hangzhou, China.",
    "Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou, China.",
    "Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education) of the Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.",
    "Cancer Center, Zhejiang University, Hangzhou, China. rhzhou@zju.edu.cn.",
    "Institute of Biophysics, College of Life Sciences, Zhejiang University, Hangzhou, China. rhzhou@zju.edu.cn.",
    "Shanghai Institute for Advanced Study, Zhejiang University, Shanghai, China. rhzhou@zju.edu.cn.",
    "Institute of Quantitative Biology, Zhejiang University, Hangzhou, China. rhzhou@zju.edu.cn.",
    "Cancer Center, Zhejiang University, Hangzhou, China. xinhan@zju.edu.cn.",
    "Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education) of the Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. xinhan@zju.edu.cn.",
    "Department of Surgical Oncology, and Pediatric Cancer Research Center, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Children and Adolescents' Health and Diseases, Hangzhou, China. xuliang.phd@zju.edu.cn.",
    "Cancer Center, Zhejiang University, Hangzhou, China. xuliang.phd@zju.edu.cn.",
    "Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou, China. xuliang.phd@zju.edu.cn.",
    "Department of Radiation Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. xuliang.phd@zju.edu.cn."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Ye Chen",
      "orcid": "0000-0003-0357-1434"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Long Xie"
    },
    {
      "affs": [
        4
      ],
      "name": "Xian Guan"
    },
    {
      "affs": [
        3
      ],
      "name": "Xingze Huang"
    },
    {
      "affs": [
        2
      ],
      "name": "Jiangyu Liu"
    },
    {
      "affs": [
        3
      ],
      "name": "Zhipeng Zhu"
    },
    {
      "affs": [
        2
      ],
      "name": "Yuanfang Wu"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Hanjun Guo"
    },
    {
      "affs": [
        4
      ],
      "name": "Lin Ma"
    },
    {
      "affs": [
        3
      ],
      "name": "Ying Zhang"
    },
    {
      "affs": [
        2
      ],
      "name": "Jiawei Zhou"
    },
    {
      "affs": [
        2
      ],
      "name": "Suya Zheng"
    },
    {
      "affs": [
        5,
        6,
        7,
        8
      ],
      "name": "Ruhong Zhou",
      "orcid": "0000-0001-8624-5591"
    },
    {
      "affs": [
        9,
        10
      ],
      "name": "Xin Han"
    },
    {
      "affs": [
        11,
        12,
        13,
        14
      ],
      "name": "Liang Xu",
      "orcid": "0000-0002-2700-4840"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6rrhwyr32cr7p.bib",
  "cited_by": 1,
  "doi": "10.1038/s41419-026-09134-w",
  "fulltext_url": "https://europepmc.org/articles/PMC13720051",
  "id": "6rrhwyr32cr7p",
  "issns": [
    "2041-4889"
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  "landing_url": "https://europepmc.org/article/MED/42957651",
  "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",
      "Article"
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      "1312|Protein Degradation and Inhibitors"
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  "pdf_url": "https://europepmc.org/articles/PMC13720051?pdf=render",
  "pmcid": "PMC13720051",
  "pmid": "42957651",
  "published": "2026-08-01",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/6rrhwyr32cr7p.ris",
  "sources": [
    {
      "first_seen": "2026-11-01T00:20:47Z",
      "native_id": "MED:42957651",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42957651"
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    {
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      "native_id": "PMC13720051",
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      "url": "https://doi.org/10.1038/s41419-026-09134-w"
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Protein Degradation and Inhibitors",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Targeted degradation of P-TEFb via MDM2 substrate substitution collapses oncogenic transcriptional programs in MDM2-amplified cancers.",
  "title_text": "Targeted degradation of P-TEFb via MDM2 substrate substitution collapses oncogenic transcriptional programs in MDM2-amplified cancers.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T12:21:00Z",
  "url": "https://research.draconitic.com/paper/6rrhwyr32cr7p",
  "venue": "Cell death & disease",
  "versions": []
}