Cancer Therapy by Targeting Thioredoxin Reductase Based on Selenium-Containing Dynamic Covalent Bond

Shuojiong Pan, Jichun Yang, Shaobo Ji, Tianyu Li, Shiqian Gao, Chenxing Sun, Huaping Xu

CCS Chem.; 2020, 2, 225–235.

Thioredoxin Reductase (TrxR) plays a pivotal role in defending cells against reactive oxygen species (ROS) and maintaining a reduced intracellular environment. It has been discovered that TrxR is elevated significantly in human cancer, evidenced by its association with the promotion of tumor cell proliferation, inhibiting tumor cell apoptosis, as well as enhancing tumor drug resistance. Hence, finding highly selective
inhibitors of TrxR is urgently needed. Herein, we developed a selenium-containing small molecule (EbD), which had two Se–N bonds. Under reduction conditions, the two Se–N bonds reacted with Se–H bond and S–H bond in TrxR to form new Se–Se bond and Se–S bonds, respectively. Subsequently, the newly formed bonds were able to disrupt the thioredoxin (Trx) reduction catalytic cycle, and thus, inhibited the
TrxR activity irreversibly, which resulted in the collapse of the antioxidant system. As a consequence, OS levels elevated that triggered cancer cell apoptosis. This strategy, based on selenium-containingdynamic covalent bonds, provides a new avenue for cancer therapy via targeting TrxR.

Pan SJ CCS Chemistry