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The ATP-binding cassette transporter ABCG2 mediates the efflux of several chemotherapeutic drugs, contributing to the development of multidrug resistance (MDR) in many cancers. The most promising strategy to overcome ABCG2-mediated MDR is the use of specific inhibitors. Despite many efforts, the identification of new potent and specific ABCG2 inhibitors remains urgent. In this study, a structural optimization of indeno[1,2- b ]indole was performed and a new generation of 18 compounds was synthesized and tested as ABCG2 inhibitors. Most compounds showed ABCG2 inhibition with IC 50  values below 0.5 µM. The ratio between cytotoxicity (IG 50 ) and ABCG2 inhibition potency (IC 50 ) was used to identify the best inhibitors. In addition, it was observed that some indeno[1,2- b ]indole derivatives produced complete inhibition, while others only partially inhibited the transport function of ABCG2. All indeno[1,2- b ]indole derivatives are not transported by ABCG2, and even the partial inhibitors are able to fully chemosensitize cancer cells overexpressing ABCG2. The high affinity of these indeno[1,2- b ]indole derivatives was confirmed by the strong stimulatory effect on ABCG2 ATPase activity. These compounds did not affect the binding of conformation-sensitive antibody 5D3 binding, but stabilized the protein structure, as revealed by the thermostabilization assay. Finally, a docking study showed the indeno[1,2- b ]indole derivatives share the same binding site as the substrate estrone-3-sulfate.

Mechanistic basis of breast cancer resistance protein inhibition by new indeno[1,2-b]indoles