期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 211, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2020.113017
关键词
Indenoindole; Dimers; Human breast cancer resistance protein; Selectivity; Uncompetitive; Nanomolar; Docking
资金
- CNRS
- Auvergne-Rhone-Alpes Region [16 013104 01 ARC SANTE 2016]
- Ligue contre le cancer
- Brazilian CNPq (Science without Borders Program) [2014-3/2014-5]
- [OTKA/NKFIH 115375]
New dimeric inhibitors targeting BCRP/ABCG2 were designed with high potency and therapeutic ratio, showing specificity in inhibiting drug efflux. The study suggests that the non-competitive mechanism by which substrate promotes inhibitor binding may be useful for targeting anticancer drug efflux.
Multidrug resistance membrane pumps reduce the efficacy of chemotherapies by exporting a wide panel of structurally-divergent drugs. Here, to take advantage of the polyspecificity of the human Breast Cancer Resistance Protein (BCRP/ABCG2) and the dimeric nature of this pump, new dimeric indenoindole-based inhibitors from the monomeric alpha,beta-unsaturated ketone 4b and phenolic derivative 5a were designed. A library of 18 homo/hetero-dimers was synthesised. Homo-dimerization shifted the inhibition efficacy from sub-micromolar to nanomolar range, correlated with the presence of 5a, linked by a 2-6 methylene-long linker. Non-toxic, the best dimers displayed a therapeutic ratio as high as 70,000. It has been found that the high potency of the best compound 7b that displays a K-I of 17 nM is due to an uncompetitive behavior toward mitoxantrone efflux and specific for that drug, compared to Hoechst 33342 efflux. Such property may be useful to target such anticancer drug efflux mediated by ABCG2. Finally, at a molecular level, an uncompetitive mechanism by which substrate promotes inhibitor binding implies that at least 2 ligands should bind simultaneously to the drug-binding pocket of ABCG2. (C) 2020 Elsevier Masson SAS. All rights reserved.
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