TranslationalResearch on the Oral Delivery of theCytotoxic PROTAC Molecule via Tumor-Targeting Prodrug Strategy forTriple-Negative Breast Cancer Treatment

作者：Huayu Hu, Yubo Wang, Mengmeng Wang, Zixuan Zhang, Xiaoting Gu, Rui‐xia Sun, Xinqiang Liu, Ning Li, Na Ding, Weiya Li, Xingli Zhao, Chao Li, Ziqi Huang, Xin Wang, Xiru Li, Shuangwei Liu, Shuang Yang, Guang Yang · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c01640 · 被引用次数：4 · 研究领域：Protein Degradation and Inhibitors、Peptidase Inhibition and Analysis、CAR-T cell therapy research

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.