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 21 possessed low cytotoxicity, high reversal potency, and good lipid
distribution coefficient. 21 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 21 can significantly improve the
oral bioavailability of paclitaxel (PTX). It was also demonstrated
that 21 significantly inhibited the growth of K562/A02
xenograft tumors by increasing the sensitivity of ADM in vivo. In summary, 21 has the potential to overcome MDR caused
by P-gp and BCRP and to improve the oral bioavailability of PTX.