{
  "abstract": "Previous studies highlight the therapeutic promise of inhibiting cyclin-dependent kinases 12 and 13 (CDK12/13) for castration-resistant prostate cancer (CRPC) and other malignancies. However, developing small molecule modulators of CDK12/13 that exhibit an optimal combination of potency, selectivity and favorable pharmacokinetics (PK) remains challenging. In this study, we present ZLC853, a potent, selective, and orally bioavailable covalent inhibitor of CDK12/13 developed through PK-oriented optimization of our previously reported inhibitor YJZ5118. ZLC853 potently inhibited CDK12 and CDK13 with IC50 values of 40.0 and 18.2 nmol/L, respectively, and displayed exceptional kinase selectivity in a comprehensive KinomeScan assay. Its covalent binding mechanism was unequivocally validated through mass spectrometry, co-crystal structure analysis, cellular pull-down assays, and washout experiments. Functionally, ZLC853 suppressed the transcription of DNA damage response genes, induced DNA damage, and promoted apoptosis. Additionally, ZLC853 exhibited good oral bioavailability and robust antitumor activity across multiple prostate cancer models, both in vitro and in vivo, supporting it as a promising candidate for clinical investigation.",
  "abstract_shown": true,
  "affiliations": [
    "State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China",
    "Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA",
    "National Facility for Protein Science in Shanghai, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai 201210, China",
    "International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, Guangzhou 511400, China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 26,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Kaijie Zhou"
    },
    {
      "affs": [
        0
      ],
      "name": "Licheng Zhou"
    },
    {
      "affs": [
        1
      ],
      "name": "Jean C. Tien"
    },
    {
      "affs": [
        0
      ],
      "name": "Weixue Huang"
    },
    {
      "affs": [
        0
      ],
      "name": "Wenyan Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Xinyu Sun"
    },
    {
      "affs": [
        0
      ],
      "name": "Bohai Fan"
    },
    {
      "affs": [
        0
      ],
      "name": "Xin Huang"
    },
    {
      "affs": [
        0
      ],
      "name": "Jun Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Yu Chang"
    },
    {
      "affs": [
        0
      ],
      "name": "Jianzhang Yang"
    },
    {
      "affs": [
        2
      ],
      "name": "Yue Yin"
    },
    {
      "affs": [
        2
      ],
      "name": "Chen Su"
    },
    {
      "affs": [
        2
      ],
      "name": "Qingrun Li"
    },
    {
      "affs": [
        1
      ],
      "name": "Rahul Mannan"
    },
    {
      "affs": [
        1
      ],
      "name": "Somnath Mahapatra"
    },
    {
      "affs": [
        1
      ],
      "name": "Yunhui Cheng"
    },
    {
      "affs": [
        1
      ],
      "name": "Abigail J. Todd"
    },
    {
      "affs": [
        1
      ],
      "name": "Christina E. Wheeler"
    },
    {
      "affs": [
        1
      ],
      "name": "Shuqin Li"
    },
    {
      "affs": [
        3
      ],
      "name": "Yang Zhou"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiaomei Ren"
    },
    {
      "affs": [
        1
      ],
      "name": "George Xiaoju Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhen Wang"
    },
    {
      "affs": [
        1
      ],
      "name": "Arul M. Chinnaiyan"
    },
    {
      "affs": [
        0
      ],
      "name": "Ke Ding"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1znq23zt3y54z.bib",
  "cited_by": 0,
  "doi": "10.1016/j.apsb.2026.07.041",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13729719/?tool=EBI",
  "id": "1znq23zt3y54z",
  "issns": [
    "2211-3835",
    "2211-3843"
  ],
  "landing_url": "https://europepmc.org/article/PMC/PMC13729719",
  "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",
      "Original Article"
    ],
    [
      "openalex",
      "1306|Prostate Cancer Treatment and Research"
    ]
  ],
  "openalex": "W7171636606",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13729719/pdf/?tool=EBI",
  "pmcid": "PMC13729719",
  "pmid": "42979420",
  "published": "2026-07-29",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/1znq23zt3y54z.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T15:20:47Z",
      "native_id": "PMC:PMC13729719",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13729719"
    },
    {
      "first_seen": "2026-11-07T12:22:28Z",
      "native_id": "PMC13729719",
      "source": "pmc",
      "url": "https://doi.org/10.1016/j.apsb.2026.07.041"
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:1306|Prostate Cancer Treatment and Research",
      "subfield": "oncology"
    }
  ],
  "title": "Discovery and preclinical evaluation of ZLC853 as a potential clinical candidate covalently targeting CDK12/13 kinases",
  "title_text": "Discovery and preclinical evaluation of ZLC853 as a potential clinical candidate covalently targeting CDK12/13 kinases",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T12:22:28Z",
  "url": "https://research.draconitic.com/paper/1znq23zt3y54z",
  "venue": "Acta pharmaceutica Sinica. B",
  "versions": []
}