4‑Anilino-2-pyridylquinazolines and -pyrimidines as Highly Potent and Nontoxic Inhibitors of Breast Cancer Resistance Protein (ABCG2)

Multidrug
resistance (MDR) mediated by ATP-binding cassette (ABC)
transport proteins remains a major problem in the chemotherapeutic
treatment of cancer and might be overcome by inhibition of the transporter.
Because of the lack of understanding, the complex mechanisms involved
in the transport process, in particular for breast cancer resistance
protein (BCRP/ABCG2), there is a persistent need for studies of inhibitors
of ABCG2. In this study, we investigated a systematic series of 4-substituted-2-pyridylquinazolines
in terms of their inhibitory potency as well as selectivity toward
ABCG2. For comparison, the quinazoline scaffold was reduced to the
significantly smaller 4-methylpyrimidine basic structure. Furthermore,
the cytotoxicity and the ability to reverse MDR was tested with the
chemotherapeutic agents SN-38 and mitoxantrone (MX). Interaction of
the compounds with ABCG2 was investigated by a colorimetric ATPase
assay. Enzyme kinetic studies were carried out with Hoechst 33342
as fluorescent dye and substrate of ABCG2 to elucidate the compounds
binding modes.