Converting potent indeno[1,2-b]indole inhibitors of protein kinase CK2 into selective inhibitors of the breast cancer resistance protein ABCG2

Gozzi GJ, Bouaziz Z, Winter E, Daflon-Yunes N, Aichele D, Nacereddine A, Marminon C, Valdameri G, Zeinyeh W, Bollacke A, Guillon J, Lacoudre A, Pinaud N, Cadena S, Jose J, Le Borgne M, Di Pietro A

Abstract

A series of indeno[1,2-b]indole-9,10-dione derivatives weresynthesized as human casein kinase II (CK2) inhibitors. The most potentinhibitors contained a N5-isopropyl substituent on the C-ring. The sameseries of compounds was found to also inhibit the breast cancer resistanceprotein ABCG2 but with totally different structure−activity relationships: aN5-phenethyl substituent was critical, and additional hydrophobic substituentsat position 7 or 8 of the D-ring or a methoxy at phenethyl positionortho or meta also contributed to inhibition. The best ABCG2 inhibitors,such as 4c, 4h, 4i, 4j, and 4k, behaved as very weak inhibitors of CK2,whereas the most potent CK2 inhibitors, such as 4a, 4p, and 4e, displayedlimited interaction with ABCG2. It was therefore possible to convert, throughsuitable substitutions of the indeno[1,2-b]indole-9,10-dione scaffold, potentCK2 inhibitors into selective ABCG2 inhibitors and vice versa. In addition,some of the best ABCG2 inhibitors, which displayed a very low cytotoxicity, thus giving a high therapeutic ratio, and appearednot to be transported, constitute promising candidates for further investigations.