Chromones bearing amino acid residues: Easily accessible and potent inhibitors of the breast cancer resistance protein ABCG2

International audienceThe Breast Cancer Resistance Protein (BCRP/ABCG2) belongs to the G class of ABC (ATP-Binding Cassette)proteins, which is known as one of the main transporters involved in the multidrug resistance (MDR)phenotype that confer resistance to anticancer drugs. The aim of this study was to design, synthesize anddevelop new potent and selective inhibitors of BCRP that can be used to abolish MDR and potentializeclinically used anticancer agents. In previous reports, we showed the importance of chromone scaffoldand hydrophobicity for the inhibition of ABC transporters. In the present study we report the design anddevelopment of chromones linked to one or two amino acids residues that are either hydrophobic orfound in the structure of FTC, one of most potent (but highly toxic) inhibitors of BCRP. Herewith, wereport the synthesis and evaluation of 13 compounds. The studied molecules were found to be not toxicand showed strong inhibition activity as well as high selectivity toward BCRP. The highest activity wasobtained with the chromone bearing a valine residue (9c) which showed an inhibition activity againstBCRP of 50 nM. The rationalization of the inhibition potential of the most active derivatives was performedthrough docking studies. Taken together, the ease of synthesis and the biological profile of thesecompounds render them as promising candidates for further development in the field of anticancertherapy