title: Potent and selective inhibitors of breast cancer resistance protein (ABCG2) derived from the p-glycoprotein (ABCB1) modulator tariquidar.
abstract: The efflux pumps ABCB1 (p-gp, MDR1) and ABCG2 (BCRP) are expressed to a high extent by endothelial cells at the blood-brain barrier (BBB) and other barrier tissues and are involved in drug resistance of tumor (stem) cells. Whereas numerous ABCB1 inhibitors are known, only a few ABCG2 modulators with submicromolar activity have been published. Starting from tariquidar (4) analogues as ABCB1 modulators, minimal structural modifications resulted in a drastic shift in favor of ABCG2 inhibition. Highest potency was found when the 3,4-dimethoxy-2-(quinoline-3-carbonylamino)benzoyl moiety in 4 was replaced with a 4-methoxycarbonylbenzoyl moiety bearing a hetarylcarboxamido group in 3-position, e.g., quinoline-3-carboxamido (5, IC(50): 119 nM) or quinoline-2-carboxamido (6, IC(50): 60 nM, flow cytometric mitoxantrone efflux assay, topotecan-resistant MCF-7 breast cancer cells); the selectivity for ABCG2 over ABCB1 was about 100-500 fold and the compounds were inactive at ABCC2 (MRP2). Chemosensitivity assays against MCF-7/Topo cells revealed that the nontoxic inhibitor 6 completely reverted ABCG2-mediated topotecan resistance at concentrations >100 nM, whereas 5 showed ABCG2 independent cytotoxicity. ABCG2 inhibitors might be useful for cancer treatment with respect to reversal of multidrug resistance, overcoming the BBB and targeting of tumor stem cells.
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, D-93053 Regensburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kühnle
authors.forename: Michael
authors.initials: M
authors.lastname: Egger
authors.forename: Christine
authors.initials: C
authors.lastname: Müller
authors.forename: Anne
authors.initials: A
authors.lastname: Mahringer
authors.forename: Günther
authors.initials: G
authors.lastname: Bernhardt
authors.forename: Gert
authors.initials: G
authors.lastname: Fricker
authors.forename: Burkhard
authors.initials: B
authors.lastname: König
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D000089762:Multidrug Resistance-Associated Protein 2; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D000089762:Multidrug Resistance-Associated Protein 2; D009363:Neoplasm Proteins; D011804:Quinolines; C402343:tariquidar