Ren Hui, Wang Yu-Jue, Wang Xin-Ye, Li Xiangyun, Han Zheng, Zhang Guxue, Gu Liwei, Bai Ming, Yao Guo-Dong, Liu Qingbo, Song Shao-Jiang
Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province; Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province; Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
Institute of Chinese Materia Medica, Artemisinin Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China.
J Med Chem. 2025 Feb 13;68(3):3088-3122. doi: 10.1021/acs.jmedchem.4c02334. Epub 2025 Jan 27.
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 exhibited potent cytotoxicity against NSCLC cells and better release rates in response to ROS. The active compound released from 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 exhibited significant antitumor efficiency in nude mice and NSCLC organoids. Our results deliver ROS-triggered prodrug 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（TrxR1）因其在非小细胞肺癌（NSCLC）细胞中的过表达，成为NSCLC治疗的重要靶点。在本研究中，为解决含α-亚甲基-γ-内酯部分的倍半萜内酯易被内源性亲核试剂快速代谢这一缺陷，基于活性氧（ROS）触发的前药策略设计并合成了一系列新型硫醚衍生物。其中，前药对NSCLC细胞表现出强大的细胞毒性，并对ROS有更好的释放率。从 释放出的活性化合物与TrxR1上的Cys475和Sec498位点共价结合，导致TrxR1活性受到抑制，进而引起氧化还原稳态紊乱，引发细胞凋亡和铁死亡。此外，前药 在裸鼠和NSCLC类器官中表现出显著抗肿瘤效果。我们的研究结果表明，ROS触发的前药 作为一种新型TrxR1抑制剂可用于NSCLC治疗，并为癌症治疗中共价化合物的ROS激活前药提供了一种有前景的策略。
