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.

本研究中，我们鉴定得到一种可强效且选择性降解细胞周期蛋白依赖性激酶4（CDK4）、细胞周期蛋白依赖性激酶6（CDK6）与细胞周期蛋白依赖性激酶9（CDK9）的蛋白降解靶向嵌合体（PROTAC）分子，其可在低纳摩尔浓度下抑制三阴性乳腺癌（TNBC）细胞增殖。但该分子生物利用度偏低，且在实验动物体内表现出显著毒性，制约了其临床转化应用。为应对这一挑战，我们开发出一种具备口服生物利用度且可靶向肿瘤的前药，该前药可大幅降低该PROTAC化合物的全身暴露水平，同时实现显著的肿瘤特异性富集。该前药可在多种细胞系来源异种移植瘤（CDX）及患者来源异种移植瘤（PDX）模型中安全有效地抑制三阴性乳腺癌细胞增殖，有望成为三阴性乳腺癌靶向治疗的极具潜力的候选药物。