Structure-Based Discovery of Pyrimidine Aminobenzene Derivatives as Potent Oral Reversal Agents against P-gp- and BCRP-Mediated Multidrug Resistance.

Overexpression of ATP binding cassette (ABC) transporters, including P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), is an important factor leading to multidrug resistance (MDR) in cancer treatments. Three subclasses of dual inhibitors of P-gp and BCRP were designed based on the active moieties of BCRP inhibitors, tyrosine kinase inhibitors, and P-gp inhibitors, of which compound possessed low cytotoxicity, high reversal potency, and good lipid distribution coefficient. also increased the accumulation of Adriamycin (ADM) and Mitoxantrone (MX), blocked Rh123 efflux, and made no change in the protein expression of P-gp and BCRP. Importantly, coadministration of can significantly improve the oral bioavailability of paclitaxel (PTX). It was also demonstrated that significantly inhibited the growth of K562/A02 xenograft tumors by increasing the sensitivity of ADM . In summary, has the potential to overcome MDR caused by P-gp and BCRP and to improve the oral bioavailability of PTX.