2-Indolylmethylenebenzofuranones as first effective inhibitors of ABCC2

Elisabeta Baiceanu, Kim Anh Nguyen, Lucia Gonzalez-Lobato, Rachad Nasr, Hélène Baubichon-Cortay, Felicia Loghin, Marc Le Borgne, Ming Cheung Chow, Ahcène Boumendjel, Marine Peuchmaur, Pierre Falson

Research output: Journal article publicationJournal articleAcademic researchpeer-review

17 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)408-418
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Volume122
DOIs
Publication statusPublished - 1 Jan 2016

Keywords

  • ABC transporters
  • ABCC2 inhibitors
  • Aurones
  • Drug interactions
  • Indolylmethylenebenzofuranone

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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