Resistance to tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) of cancer cells is a main obstacle for the chemotherapy. NRH: quinone oxidoreductase 2 (NQO2), known as a chemopreventive target, has emerged as a promising therapeutic target for overcoming TRAIL resistance in non-small cell lung cancer (NSCLC). Here we report the design, synthesis and evaluation of resveratrol analogues as novel selective NQO2 inhibitors, and analogue 20b, with potent NQO2 inhibitory activity (IC = 95 nM) and relatively low cytotoxicity, displayed synergistic lethal effects in combination with TRAIL on TRAIL-resistant NSCLC cells. In addition, mechanistic studies revealed that 20b sensitized TRAIL-resistant A549 cells to apoptosis through the generation of reactive oxygen species (ROS) and the upregulation of death receptor 5 (DR5). Furthermore, 20b showed no acute toxicity in the healthy mice at a single dose of 2000 mg/kg. Molecular docking confirmed the binding mode of 20b within the NQO2 active site, highlighting key interactions responsible for its enhanced potency. This study provided novel molecular templates for development of NQO2 inhibitor, and laid a foundation for developing agents against TRAIL-resistant cancers for targeting NQO2.
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