2. Academic Validation
  3. 2-Indolylmethylenebenzofuranones as first effective inhibitors of ABCC2

2-Indolylmethylenebenzofuranones as first effective inhibitors of ABCC2

  • Eur J Med Chem. 2016 Oct 21:122:408-418. doi: 10.1016/j.ejmech.2016.06.039.
Elisabeta Baiceanu 1,  Kim-Anh Nguyen 2,  Lucia Gonzalez-Lobato 3,  Rachad Nasr 3,  Hélène Baubichon-Cortay 3,  Felicia Loghin 4,  Marc Le Borgne 5,  Larry Chow 6,  Ahcène Boumendjel 2,  Marine Peuchmaur 2,  Pierre Falson 7
Affiliations

Affiliations

  • 1 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.
  • 2 Univ. Grenoble Alpes, Département de Pharmacochimie Moléculaire DPM UMR 5063, 38041 Grenoble, France; CNRS, DPM UMR 5063, 38041 Grenoble, France.
  • 3 Drug Resistance Mechanisms and Membrane Proteins Laboratory, BMSSI UMR 5086 CNRS/Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France.
  • 4 Toxicology Department, Faculty of Pharmacy, Univ. Medicine and Pharmacy ¨Iuliu Hatieganu¨, Cluj-Napoca, Romania.
  • 5 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.
  • 6 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.
  • 7 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.
PMID: 27393949 DOI: 10.1016/j.ejmech.2016.06.039
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.

Keywords

ABC transporters; ABCC2 inhibitors; Aurones; Drug interactions; Indolylmethylenebenzofuranone.

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