title: New, highly potent and non-toxic, chromone inhibitors of the human breast cancer resistance protein ABCG2.
abstract: Breast cancer resistance protein (BCRP/ABCG2) is one of the major transporters involved in the efflux of anticancer compounds, contributing to multidrug resistance (MDR). Inhibition of ABCG2-mediated transport is then considered a promising strategy for overcoming MDR in tumors. We recently identified a chromone derivative, namely MBL-II-141 as a selective ABCG2 inhibitor, with relevant in vivo activity. Here, we report the pharmacomodulation of MBL-II-141, with the aim of identifying key pharmacophoric elements to design more potent selective and non-toxic inhibitors. Through rational structural modifications of MBL-II-141, using simple and affordable chemistry, we obtained highly active and easily-made inhibitors of ABCG2. Among the investigated compounds, derivative 4a, was found to be 3-fold more potent than MBL-II-141. It was similarly efficient as the reference inhibitor Ko143 but with the advantage of a lower intrinsic cytotoxicity, and therefore constitutes the best ABCG2 inhibitor ever reported displaying a very high therapeutic ratio.
authors.affiliation: Equipe Labellisée Ligue 2014 "Mécanisme et Modulation de la Résistance aux Médicaments", Université Lyon 1, Univ. Lyon, CNRS UMR 5086 Bases Moléculaires et Structurales des Systèmes Infectieux, IBCP, 7 Passage du Vercors, 69367 Lyon Cedex 07, France.
authors.forename: Amanda do Rocio Andrade
authors.initials: ADRA
authors.lastname: Pires
authors.affiliation: Université Grenoble-Alpes/CNRS, Département de Pharmacochimie Moléculaire UMR 5063, F-38041 Grenoble, France.
authors.forename: Florine
authors.initials: F
authors.lastname: Lecerf-Schmidt
authors.affiliation: Equipe Labellisée Ligue 2014 "Mécanisme et Modulation de la Résistance aux Médicaments", Université Lyon 1, Univ. Lyon, CNRS UMR 5086 Bases Moléculaires et Structurales des Systèmes Infectieux, IBCP, 7 Passage du Vercors, 69367 Lyon Cedex 07, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Guragossian
authors.affiliation: Equipe Labellisée Ligue 2014 "Mécanisme et Modulation de la Résistance aux Médicaments", Université Lyon 1, Univ. Lyon, CNRS UMR 5086 Bases Moléculaires et Structurales des Systèmes Infectieux, IBCP, 7 Passage du Vercors, 69367 Lyon Cedex 07, France.
authors.forename: Jaqueline
authors.initials: J
authors.lastname: Pazinato
authors.affiliation: Equipe Labellisée Ligue 2014 "Mécanisme et Modulation de la Résistance aux Médicaments", Université Lyon 1, Univ. Lyon, CNRS UMR 5086 Bases Moléculaires et Structurales des Systèmes Infectieux, IBCP, 7 Passage du Vercors, 69367 Lyon Cedex 07, France.
authors.forename: Gustavo Jabor
authors.initials: GJ
authors.lastname: Gozzi
authors.affiliation: Equipe Labellisée Ligue 2014 "Mécanisme et Modulation de la Résistance aux Médicaments", Université Lyon 1, Univ. Lyon, CNRS UMR 5086 Bases Moléculaires et Structurales des Systèmes Infectieux, IBCP, 7 Passage du Vercors, 69367 Lyon Cedex 07, France.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Winter
authors.affiliation: Equipe Labellisée Ligue 2014 "Mécanisme et Modulation de la Résistance aux Médicaments", Université Lyon 1, Univ. Lyon, CNRS UMR 5086 Bases Moléculaires et Structurales des Systèmes Infectieux, IBCP, 7 Passage du Vercors, 69367 Lyon Cedex 07, France.
authors.forename: Glaucio
authors.initials: G
authors.lastname: Valdameri
authors.affiliation: Université Grenoble-Alpes/CNRS, Département de Pharmacochimie Moléculaire UMR 5063, F-38041 Grenoble, France.
authors.forename: Alexander
authors.initials: A
authors.lastname: Veale
authors.affiliation: Université Grenoble-Alpes/CNRS, Département de Pharmacochimie Moléculaire UMR 5063, F-38041 Grenoble, France.
authors.forename: Ahcène
authors.initials: A
authors.lastname: Boumendjel
authors.affiliation: Equipe Labellisée Ligue 2014 "Mécanisme et Modulation de la Résistance aux Médicaments", Université Lyon 1, Univ. Lyon, CNRS UMR 5086 Bases Moléculaires et Structurales des Systèmes Infectieux, IBCP, 7 Passage du Vercors, 69367 Lyon Cedex 07, France.
authors.forename: Attilio
authors.initials: A
authors.lastname: Di Pietro
authors.affiliation: Université Grenoble-Alpes/CNRS, Département de Pharmacochimie Moléculaire UMR 5063, F-38041 Grenoble, France. Electronic address: Basile.Peres@univ-grenoble-alpes.fr.
authors.forename: Basile
authors.initials: B
authors.lastname: Pérès
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000037:antagonists & inhibitors*; D001943:Breast Neoplasms; D002867:Chromones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D013329:Structure-Activity Relationship
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D002867:Chromones
keywords: ABCG2 modulators; Chemoresistance; Chromones; Efflux