2. Academic Validation
  3. Translational Research on the Oral Delivery of the Cytotoxic PROTAC Molecule via Tumor-Targeting Prodrug Strategy for Triple-Negative Breast Cancer Treatment

Translational Research on the Oral Delivery of the Cytotoxic PROTAC Molecule via Tumor-Targeting Prodrug Strategy for Triple-Negative Breast Cancer Treatment

  • J Med Chem. 2025 Oct 9;68(19):20464-20486. doi: 10.1021/acs.jmedchem.5c01640.
Huayu Hu 1,  Yubo Wang 1,  Mengmeng Wang 1,  Zixuan Zhang 1,  Xiaoting Gu 1,  Ruixia Sun 2 3,  Xinqiang Liu 1,  Ning Li 1,  Na Ding 1,  Weiya Li 3,  Xingli Zhao 3,  Chao Li 3,  Ziqi Huang 1,  Xin Wang 1,  Xiru Li 4,  Shuangwei Liu 1,  Shuang Yang 1,  Guang Yang 1
Affiliations

Affiliations

  • 1 State Key Lab of Medicinal Chemical Biology, School of Medicine, College of Pharmacy, Nankai University, Tianjin 300071, China.
  • 2 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
  • 3 Department of Hematology, Department of Pharmacy, Department of General Surgery, Oncology Center, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, Tianjin 300121, China.
  • 4 Department of General Surgery, The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing 100853, China.
PMID: 40977512 DOI: 10.1021/acs.jmedchem.5c01640
Abstract

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 in vivo 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.

Figures
Products