Inhibition of TGFβ signaling in concert with a checkpoint blockade has been shown to provide improved and durable antitumor immune response in mouse models. However, on-target adverse cardiovascular effects have limited the clinical use of TGFβ receptor (TGFβR) inhibitors in cancer therapy. To restrict the activity of TGFβR inhibitors to tumor tissues and thereby widen the therapeutic index, a series of tumor-activated prodrugs of a selective small molecule TGFβR1 inhibitor 1 were prepared by appending 1 to a serine protease substrate and a half-life extension fatty acid carbon chain. The prodrugs were shown to be selectively metabolized in tumor tissues relative to the heart and blood and demonstrated a prolonged favorable increase in the tumor-to-heart ratio of the active drug in tissue distribution studies. Once-weekly administration of the most tissue-selective compound 10 provided anti-tumor efficacy comparable to the parent compound and reduced systemic exposure of the active drug.

中文翻译：

---

TGFβR抑制剂的长效肿瘤激活前药

已显示抑制 TGFβ 信号传导与检查点阻断相结合可在小鼠模型中提供改善和持久的抗肿瘤免疫反应。然而，靶向性心血管不良反应限制了 TGFβ 受体 (TGFβR) 抑制剂在癌症治疗中的临床应用。为了限制 TGFβR 抑制剂对肿瘤组织的活性，从而扩大治疗指数，通过附加1制备了一系列选择性小分子 TGFβR1 抑制剂1的肿瘤激活前药。丝氨酸蛋白酶底物和半衰期延长脂肪酸碳链。相对于心脏和血液，前药被证明在肿瘤组织中选择性代谢，并在组织分布研究中显示出活性药物的肿瘤与心脏比率的长期有利增加。每周一次施用最具组织选择性的化合物10提供了与母体化合物相当的抗肿瘤功效并减少了活性药物的全身暴露。