title: 2-Indolylmethylenebenzofuranones as first effective inhibitors of ABCC2.
abstract: ABC-transporters play a vital role in drugs bioavailability. They prevent intracellular accumulation of toxic compounds, rendering them a major defense mechanism against harmful substances. In this large family, ABCC2 is an apical efflux pump representing about 10% of all membrane proteins in liver and small intestine, and up to 25% in colon. In these tissues, ABCC2 plays a major role in the pharmacokinetics and pharmacodynamics of endo- and xenobiotics. To gain insight in the function of this crucial protein, we have investigated and developed the first effective inhibitors of this pump. Firstly, we set up a cellular flow cytometry assay for monitoring the drug efflux carried out by ABCC2, and used it for the screening of chemical libraries derived from several chemical classes. We found that 2-indolylmethylenebenzofuranone derivatives as promising candidates. Optimization of the hits provided new compounds that inhibit ABCC2 in the micromolar range, making them the first potent ABCC2 inhibitors reported so far. Such compounds would constitute valuable tools to further investigate the role of ABCC2 in the pharmacokinetics and pharmacodynamics of drugs.
authors.affiliation: Drug Resistance Mechanisms and Membrane Proteins Laboratory, BMSSI UMR 5086 CNRS/Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France; Toxicology Department, Faculty of Pharmacy, Univ. Medicine and Pharmacy ¨Iuliu Hatieganu¨, Cluj-Napoca, Romania.
authors.forename: Elisabeta
authors.initials: E
authors.lastname: Baiceanu
authors.affiliation: Univ. Grenoble Alpes, Département de Pharmacochimie Moléculaire DPM UMR 5063, 38041 Grenoble, France; CNRS, DPM UMR 5063, 38041 Grenoble, France.
authors.forename: Kim-Anh
authors.initials: KA
authors.lastname: Nguyen
authors.affiliation: Drug Resistance Mechanisms and Membrane Proteins Laboratory, BMSSI UMR 5086 CNRS/Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France.
authors.forename: Lucia
authors.initials: L
authors.lastname: Gonzalez-Lobato
authors.affiliation: Drug Resistance Mechanisms and Membrane Proteins Laboratory, BMSSI UMR 5086 CNRS/Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France.
authors.forename: Rachad
authors.initials: R
authors.lastname: Nasr
authors.affiliation: Drug Resistance Mechanisms and Membrane Proteins Laboratory, BMSSI UMR 5086 CNRS/Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Baubichon-Cortay
authors.affiliation: Toxicology Department, Faculty of Pharmacy, Univ. Medicine and Pharmacy ¨Iuliu Hatieganu¨, Cluj-Napoca, Romania.
authors.forename: Felicia
authors.initials: F
authors.lastname: Loghin
authors.affiliation: Université de Lyon, Université Lyon 1, Faculté de Pharmacie - ISPB, EA 4446 Bioactive Molecules and Medicinal Chemistry, SFR Santé Lyon-Est CNRS UMS3453 - INSERM US7, 8 Avenue Rockefeller, F-69373 Lyon Cedex 8, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Le Borgne
authors.affiliation: Department of Applied Biology and Chemical Technology, and State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hung Hom, Hong Kong Special Administrative Region.
authors.forename: Larry
authors.initials: L
authors.lastname: Chow
authors.affiliation: Univ. Grenoble Alpes, Département de Pharmacochimie Moléculaire DPM UMR 5063, 38041 Grenoble, France; CNRS, DPM UMR 5063, 38041 Grenoble, France.
authors.forename: Ahcène
authors.initials: A
authors.lastname: Boumendjel
authors.affiliation: Univ. Grenoble Alpes, Département de Pharmacochimie Moléculaire DPM UMR 5063, 38041 Grenoble, France; CNRS, DPM UMR 5063, 38041 Grenoble, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Peuchmaur
authors.affiliation: Drug Resistance Mechanisms and Membrane Proteins Laboratory, BMSSI UMR 5086 CNRS/Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France. Electronic address: pierre.falson@ibcp.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Falson
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D004285:Dogs; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D041681:NIH 3T3 Cells
chemical_list: D001572:Benzofurans; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins
keywords: ABC transporters; ABCC2 inhibitors; Aurones; Drug interactions; Indolylmethylenebenzofuranone