Design of ROS-Triggered Sesquiterpene Lactone SC Prodrugs as TrxR1 Covalent Inhibitors for the Treatment of Non-Small Cell Lung Cancer

Thioredoxin reductase 1 (TrxR1) is an important therapeutic target for nonsmall cell lung cancer (NSCLC) treatment due to its overexpression in NSCLC cells. In this work, to address the deficiency that sesquiterpene lactone containing α-methylene-γ-lactone moiety was rapidly metabolized by endogenous nucleophiles, series of novel thioether derivatives were designed and synthesized based on a reactive oxygen species (ROS)-triggered prodrug strategy. Among them, prodrug 5u exhibited potent cytotoxicity against NSCLC cells and better release rates in response to ROS. The active compound 6a released from 5u covalently binds to Cys475 and Sec498 sites on TrxR1, resulting in inhibition on TrxR1 activity, which led to redox homeostasis disorder, and caused apoptosis and ferroptosis. Moreover, prodrug 5u exhibited significant antitumor efficiency in nude mice and NSCLC organoids. Our results deliver ROS-triggered prodrug 5u as a novel TrxR1 inhibitor for the treatment of NSCLC and provide a promising strategy of ROS-activated prodrug for covalent compounds in cancer therapy.

硫氧还蛋白还原酶1（Thioredoxin reductase 1, TrxR1）因在非小细胞肺癌（non-small cell lung cancer, NSCLC）细胞中高表达，成为非小细胞肺癌治疗的重要靶点。本研究针对含有α-亚甲基-γ-内酯结构的倍半萜内酯易被内源性亲核试剂快速代谢的缺陷，基于活性氧（reactive oxygen species, ROS）触发型前药策略，设计并合成了一系列新型硫醚衍生物。其中，前药5u对非小细胞肺癌细胞展现出强效细胞毒性，且在活性氧刺激下具备更优异的药物释放性能。由5u释放的活性化合物6a可共价结合于TrxR1的Cys475与Sec498位点，抑制TrxR1活性，进而引发氧化还原稳态失衡，诱导细胞凋亡与铁死亡。此外，前药5u在裸鼠及非小细胞肺癌类器官模型中均表现出显著的抗肿瘤活性。本研究证实，ROS触发型前药5u可作为新型TrxR1抑制剂用于非小细胞肺癌治疗，同时为癌症治疗中共价类化合物的ROS激活型前药策略提供了极具潜力的研究方向。