Artigo Acesso aberto Produção Nacional Revisado por pares

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

2020; Elsevier BV; Volume: 211; Linguagem: Inglês

10.1016/j.ejmech.2020.113017

ISSN

1768-3254

Autores

Nathalie Guragossian, Billel Belhani, Alexis Moréno, Magda Teixeira-Nunes, Lucía González-Lobato, Christelle Marminon, Laurent Berthier, Amanda do Rocio Andrade Pires, Csilla Özvegy‐Laczka, Balázs Sarkadi, Raphaël Terreux, Zouhair Bouaziz, Malika Berredjem, Joachim Jose, Attilio Di Pietro, Pierre Falson, Marc Le Borgne,

Tópico(s)

Cancer therapeutics and mechanisms

Resumo

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.

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