Uncompetitive nanomolar dimeric indenoindole inhibitors of the human breast cancer resistance pump ABCG2 - Université Claude Bernard Lyon 1 Accéder directement au contenu
Article Dans Une Revue European Journal of Medicinal Chemistry Année : 2021

Uncompetitive nanomolar dimeric indenoindole inhibitors of the human breast cancer resistance pump ABCG2

Malika Berredjem

Résumé

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 α,β-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 KI 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.
Fichier principal
Vignette du fichier
S0223523420309892.pdf (1 Mo) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-03032952 , version 1 (13-02-2023)

Licence

Paternité - Pas d'utilisation commerciale

Identifiants

Citer

Nathalie Guragossian, Billel Belhani, Alexis Moreno, Magda Teixeira Nunes, Lucia Gonzalez-Lobato, et al.. Uncompetitive nanomolar dimeric indenoindole inhibitors of the human breast cancer resistance pump ABCG2. European Journal of Medicinal Chemistry, 2021, 211, pp.113017. ⟨10.1016/j.ejmech.2020.113017⟩. ⟨hal-03032952⟩
76 Consultations
16 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More