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

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-]pyrimidine-based compound as a highly potent, specific, and orally active P-gp inhibitor. Through direct binding to P-gp, 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. 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, displayed minimal effect on the drug-metabolizing enzyme cytochrome P4503A4 (CYP3A4). Importantly, increased sensitivity of both pre-clinically and clinically derived MDR tumors to PTX with the T/C value of 29.7% in patient-derived xenograft (PDX) models. Relative to PTX treatment alone, combination of and PTX caused no obvious adverse reactions. Taken together, our preclinical studies revealed therapeutic promise of against MDR cancer, the promising data warrant its further development for cancer therapy.