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 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.