2-Indolylmethylenebenzofuranones as first effective inhibitors of ABCC2
2016; Elsevier BV; Volume: 122; Linguagem: Inglês
10.1016/j.ejmech.2016.06.039
ISSN1768-3254
AutoresElisabeta Baiceanu, Kim‐Anh Nguyen, Lucía González-Lobato, Rachad Nasr, Hélène Baubichon‐Cortay, Felicia Loghin, Marc Le Borgne, Larry M. C. Chow, A. Boumendjel, Marine Peuchmaur, Pierre Falson,
Tópico(s)Pregnancy and Medication Impact
ResumoABC-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.
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