摘要Multidrug resistance(MDR)is the main cause of clinical treatment failure and poor prog-nosis in cancer.Targeting P-glycoprotein(P-gp)has been regarded as an effective strategy to overcome MDR.In this work,we reported our preclinical studies of the triazolo[1,5-a]pyrimidine-based compound WS-716 as a highly potent,specific,and orally active P-gp inhibitor.Through direct binding to P-gp,WS-716 inhibited efflux function of P-gp and specifically reversed P-gp-mediated MDR to paclitaxel(PTX)in multiple resistant cell lines,without changing its expression or subcellular localization.WS-716 and PTX synergistically inhibited formation of colony and 3D spheroid,induced apoptosis and cell cycle arrest at G2/M phase in resistant SW620/Ad300 cells.In addition,WS-716 displayed minimal ef-fect on the drug-metabolizing enzyme cytochrome P4503A4(CYP3A4).Importantly,WS-716 increased sensitivity of both pre-clinically and clinically derived MDR tumors to PTX in vivo with the T/C value of 29.7％in patient-derived xenograft(PDX)models.Relative to PTX treatment alone,combination of WS-716 and PTX caused no obvious adverse reactions.Taken together,our preclinical studies revealed ther-apeutic promise of WS-716 against MDR cancer,the promising data warrant its further development for cancer therapy.