title: Converting potent indeno[1,2-b]indole inhibitors of protein kinase CK2 into selective inhibitors of the breast cancer resistance protein ABCG2.
abstract: A series of indeno[1,2-b]indole-9,10-dione derivatives were synthesized as human casein kinase II (CK2) inhibitors. The most potent inhibitors contained a N(5)-isopropyl substituent on the C-ring. The same series of compounds was found to also inhibit the breast cancer resistance protein ABCG2 but with totally different structure-activity relationships: a N(5)-phenethyl substituent was critical, and additional hydrophobic substituents at position 7 or 8 of the D-ring or a methoxy at phenethyl position ortho 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, displayed limited interaction with ABCG2. It was therefore possible to convert, through suitable substitutions of the indeno[1,2-b]indole-9,10-dione scaffold, potent CK2 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 appeared not to be transported, constitute promising candidates for further investigations.
authors.affiliation: Equipe Labellisée Ligue 2014, BMSSI UMR 5086 CNRS/Université Lyon 1, IBCP, 69367 Lyon, France.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Jabor Gozzi
authors.forename: Zouhair
authors.initials: Z
authors.lastname: Bouaziz
authors.forename: Evelyn
authors.initials: E
authors.lastname: Winter
authors.forename: Nathalia
authors.initials: N
authors.lastname: Daflon-Yunes
authors.forename: Dagmar
authors.initials: D
authors.lastname: Aichele
authors.forename: Abdelhamid
authors.initials: A
authors.lastname: Nacereddine
authors.forename: Christelle
authors.initials: C
authors.lastname: Marminon
authors.forename: Glaucio
authors.initials: G
authors.lastname: Valdameri
authors.forename: Waël
authors.initials: W
authors.lastname: Zeinyeh
authors.forename: Andre
authors.initials: A
authors.lastname: Bollacke
authors.forename: Jean
authors.initials: J
authors.lastname: Guillon
authors.forename: Aline
authors.initials: A
authors.lastname: Lacoudre
authors.forename: Noël
authors.initials: N
authors.lastname: Pinaud
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Cadena
authors.forename: Joachim
authors.initials: J
authors.lastname: Jose
authors.forename: Marc
authors.initials: M
authors.lastname: Le Borgne
authors.forename: Attilio
authors.initials: A
authors.lastname: Di Pietro
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D008942:Mitoxantrone / Q000378:metabolism; D008956:Models, Chemical; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D007211:Indoles; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; C030374:indole; D008942:Mitoxantrone; D047390:Casein Kinase II