Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction.
Bioorg Med Chem Lett
; 23(10): 3039-43, 2013 May 15.
Article
em En
| MEDLINE
| ID: mdl-23562243
ABSTRACT
A high-throughput screen (HTS) of the MLPCN library using a homogenous fluorescence polarization assay identified a small molecule as a first-in-class direct inhibitor of Keap1-Nrf2 protein-protein interaction. The HTS hit has three chiral centers; a combination of flash and chiral chromatographic separation demonstrated that Keap1-binding activity resides predominantly in one stereoisomer (SRS)-5 designated as ML334 (LH601A), which is at least 100× more potent than the other stereoisomers. The stereochemistry of the four cis isomers was assigned using X-ray crystallography and confirmed using stereospecific synthesis. (SRS)-5 is functionally active in both an ARE gene reporter assay and an Nrf2 nuclear translocation assay. The stereospecific nature of binding between (SRS)-5 and Keap1 as well as the preliminary but tractable structure-activity relationships support its use as a lead for our ongoing optimization.
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Base de dados:
MEDLINE
Assunto principal:
Ftalimidas
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Sondas Moleculares
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Peptídeos e Proteínas de Sinalização Intracelular
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Fator 2 Relacionado a NF-E2
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Bibliotecas de Moléculas Pequenas
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Descoberta de Drogas
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Imagem Molecular
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Isoquinolinas
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article