Mechanistic basis of breast cancer resistance protein inhibition by new indeno[1,2-b]indoles
Diogo Henrique Kita, Nathalie Guragossian, Ingrid Fátima Zattoni, Vivian Rotuno Moure, Fabiane Gomes de Moraes Rego, Sabrina Lusvarghi, Thomas Moulenat, Billel Belhani, Geraldo Picheth, Sofiane Bouacida, Zouhair Bouaziz, Christelle Marminon, Malika Berredjem, Joachim Jose, Marcos Brown Gonçalves, Suresh V. Ambudkar, Gláucio Valdameri, Marc Le Borgne
Abstract
Abstract 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.