Abstract Reactive oxygen species (ROS) play a central role in cellular signaling and homeostasis. However, imbalances in ROS levels contribute to various pathologies, including cancer. Tumor cells often upregulate antioxidant systems, such as the thioredoxin reductase (TrxR) and glutathione (GSH) pathways, to buffer against oxidative stress. The identification of aberrant metabolism and ROS has generated excitement and promise as a hallmark targetable vulnerability of tumors. Unfortunately, despite tremendous academic and industry efforts, this promise remains unfulfilled. Here, we report the discovery of YS207, a first-in-class covalent heterobifunctional inhibitor of TrxR1 using the deubiquitinase-targeting chimera (DUBTAC) technology. YS207 is composed of TrxR1 recruiting moiety coupled to deubiquitinase recruiting moiety via a novel chemical linker resulting in stabilization of covalently inhibited TrxR1 for profound generation of therapeutic levels of ROS. YS207 treatment potently inhibited TrxR1 enzymatic activity in vitro and in vivo (IC50 of 40nM Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3079.
Han et al. (Fri,) studied this question.