Preclinical studies of the triazolo[1,5-a]pyrimidine derivative WS-716 as a highly potent, specific and orally active P-glycoprotein (P-gp) inhibitor

Preclinical studies of the triazolo[1,5-a]pyrimidine derivative WS-716 as a highly potent, specific and orally active P-glycoprotein (P-gp) inhibitor

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Multidrug resistance (MDR) is the main cause of clinical treatment failure and poor prognosis 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 lorenametaute.com 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 effect on the drug-metabolizing enzyme cytochrome arcade smokey the bear belt 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 therapeutic promise of WS-716 against MDR cancer, the promising data warrant its further development for cancer therapy.