YS207

YS207 is a first-in-class, covalent heterobifunctional inhibitor of thioredoxin reductase 1 (TrxR1) developed using deubiquitinase-targeting chimera (DUBTAC) technology. Discovered by researchers at The University of Texas MD Anderson Cancer Center, YS207 consists of a TrxR1-recruiting moiety coupled to a deubiquitinase-recruiting moiety via a novel chemical linker. Unlike traditional proteolysis-targeting chimeras (PROTACs) that induce protein degradation, YS207 utilizes the DUBTAC platform to stabilize the covalently inhibited form of TrxR1. This stabilization leads to the profound generation of therapeutic levels of reactive oxygen species (ROS), induction of lipid peroxidation, and depletion of intracellular glutathione (GSH). YS207 inhibits TrxR1 enzymatic activity with an IC50 of 40 nM in vitro and 700 nM in vivo. Mechanistically, it causes significant mitochondrial damage, including swelling, loss of cristae, and mitophagy. Preclinical evaluation in lung cancer xenograft models has demonstrated potent anti-tumor activity, with sensitivity correlating to TrxR1 dependency, NADPH metabolism, and selenoprotein biosynthesis pathways.