Targeting the multidrug ABCG2 transporter with flavonoidic inhibitors: in vitro optimization and in vivo validation

International audience; This review describes the breast cancer resistance protein ABCG2 through its structure, functional roles and involvement in cell multidrug resistance, especially in cancer cells resistance to chemotherapeutics. The different types of known inhibitors are described, some being non-selective, since they also bind to other targets, and others being quite specific such as flavonoids. The different classes of active flavonoids and other polyphenols are described, some as plant natural compounds, but most of them being prepared and derivatized through medicinal chemistry. Quantitative structure-activity relationships of the ability of flavones, chalcones, xanthones, acridones and various benzopyrane/benzofurane derivatives to inhibit ABCG2-mediated drug efflux have led to pharmacophores and molecular models allowing to optimize the available hit compounds and to design new-generation lead compounds. Interestingly, inhibitory flavonoids are quite specific for ABCG2 versus ABCB1 and ABCC1, and appear either non-competitive or partially competitive towards mitoxantrone efflux. Most compounds do not inhibit ATPase activity, and are assumed not to be transported themselves by the transporter. Some acridones, firstly optimized in vitro as potent inhibitors, are indeed efficient in vivo, against human xenografts in SCID mice, more efficiently than gefitinib taken as a control. Future developments should open the way to more efficient/targeted modulators including (i) the potential interest of bimodulation by combining two different inhibitors, (ii) computer-assisted ligand-based drug design for getting more potent and more specific inhibitors, (iii) structure-based drug design from ABCG2 molecular models allowing in silico screening and docking of new inhibitors.