Strategies to select the right indeno[1,2-b]indole derivative(s) for ABCG2-targeting in vivo assays.

Guragossian N, Gozzi G J, Bouaziz Z, Winter E, Valdameri G, Terreux R, Marminon C, Boumendje lA, Jose J, Di Pietro A, Le Borgne M

Abstract

ABCG2 is a 72kDa sub-family G member 2 of ATP-binding cassette membrane proteins that functions as an efflux pump against toxins and xenobiotics, conferring cross-resistance to several classes of anticancer chemotherapeutics.Development of ABCG2 inhibitors can be used in combination with anticancer drugs to block the drug secretion from cancer cells. Functionalized indeno[1,2-b]indoles are compounds that have already shown a good inhibitory activity against the protein Casein Kinase 2 (CK2)1 and could be converted into ABCG2 inhibitors with an IC50in thesubmicromolar range uponspecific substitutions on the C- and/or D-ring(s).2,3From such a work, some selectedindeno[1,2-b]indoles (both ketonic and phenolic derivatives) with high therapeutic index on cultured cells have been discriminated as promising candidates for in vivo evaluation.