Translational Research on the Oral Delivery of the Cytotoxic PROTAC Molecule via Tumor-Targeting Prodrug Strategy for Triple-Negative Breast Cancer Treatment
In the present work, we have identified a proteolysis targeting chimera (PROTAC) molecule that potently and selectively degrades CDK4, CDK6, and CDK9, inhibiting triple-negative breast cancer (TNBC) cell proliferation at low nanomolar concentrations. However, its low bioavailability and significant <i>in vivo</i> toxicity in experimental animals limit clinical translation. To address this challenge, we identified an oral bioavailable and tumor-targeting prodrug that substantially reduces systemic exposure of the PROTAC compound while enabling significant tumor-specific enrichment. This prodrug effectively and safely inhibits TNBC cell proliferation in multiple cell line-derived xenografts (CDX) and patient-derived xenograft (PDX) models, positioning it as a promising candidate for targeted TNBC therapy.
Authors
- Yubo Wang (ORCID: https://orcid.org/0000-0002-0895-8745)
- Xinqiang Liu (ORCID: https://orcid.org/0000-0003-1811-1617)
- Huayu Hu (ORCID: https://orcid.org/0000-0002-7632-2618)
- Shuangwei Liu
- Na Ding (ORCID: https://orcid.org/0000-0003-2343-9625)
- Shuang Yang (ORCID: https://orcid.org/0000-0002-4779-8553)
- Xiru Li (ORCID: https://orcid.org/0000-0003-1840-7522)
- Guang Yang (ORCID: https://orcid.org/0000-0002-1773-9392)
- Xiaoting Gu (ORCID: https://orcid.org/0000-0002-9236-5941)
- Zixuan Zhang (ORCID: https://orcid.org/0000-0002-1782-4108)
- Chao Li (ORCID: https://orcid.org/0000-0002-1950-0190)
- Xin Wang
- Ning Li (ORCID: https://orcid.org/0000-0002-9789-1633)
- Mengmeng Wang (ORCID: https://orcid.org/0000-0002-2425-5521)
- Ziqi Huang (ORCID: https://orcid.org/0009-0004-7820-4852)
- Weiya Li (ORCID: https://orcid.org/0000-0002-6106-8530)
- Xingli Zhao (ORCID: https://orcid.org/0009-0006-1848-1318)
- Rui‐xia Sun (ORCID: https://orcid.org/0000-0002-3646-9842)
Institutions
- Nanchang University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Nankai University (CN)
- Tianjin First Center Hospital (CN)
- Peking Union Medical College Hospital (CN)
- Tianjin Medical University General Hospital (CN)
- Chinese PLA General Hospital (CN)
- Chinese General Hospital College of Nursing and Liberal Arts (PH)
- National Clinical Research (US)
- Institute of Hematology & Blood Diseases Hospital (CN)
- State Key Laboratory of Chemical Engineering (CN)
- First Affiliated Hospital of Nanchang University (CN)
- Tianjin Medical University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-09-22
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01640
- Citations
- 2
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 1.61