Prediction of the physicochemical and ADMET properties of indeno[1,2-b]indole derivatives as potent ABCG2 inhibitors

Guragossian N, Gozzi GJ, Bouaziz Z, Winter E, Daflon-Yunes N, Honorat M, Marminon C, Terreux R, Valdameri G, Bollacke A, Guillon J, Pinaud N, Marchivie M, Cadena S, Jose J, Le Borgne M, Di Pietro A

Abstract

ABCG2 is an ATP-binding cassette sub-family G member 2 protein implicated in the transport of various molecules across extra- and intra-cellular membranes. This protein is knownto be implicated in xenobiotic transporters. Since discovering its role in multidrug resistance, numerous studies have been made in order to inhibit its function (1),(2). A series ofindeno[1,2-b]indoles previously synthesized as human casein kinase 2 (CK2) inhibitors were found to selectively inhibit ABCG2 (3).The N5-phenethyl derivatives showed IC50 values inthe submicromolar range. Twelve compounds are potent candidates for an in vivo evaluation. Our study was aimed at predicting their physico-chemical properties (Molinspirationsoftware v2013) and ADMET parameters (ACD percepta v2012, QSAR Toolbox v3.2) to help us to select the best candidate(s). We present the results obtained for the four mostrepresentative compounds.