Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory activity.
Bioorg Med Chem Lett
; 26(24): 5956-5959, 2016 12 15.
Article
em En
| MEDLINE
| ID: mdl-27839920
ABSTRACT
The Keap1-Nrf2 system is involved not only in biological defense but also in malignancy progression and chemoresistance. The ubiquitin-binding protein p62/Sqstm1 (p62), which is highly expressed in several cancers, competes with Nrf2 for Keap1 binding, leading to activation of Nrf2-mediated gene expression and survival of cancer cells. We had previously identified an inhibitor for the Keap1-phosphorylated-p62 (p-p62) protein-protein interaction (PPI), the acetonyl naphthalene derivative K67. In this study, we established facile synthetic routes for K67 and derivatives with various side chains on the C-2 position of naphthalene ring. K67 possessed high selectivity in the inhibition of Keap1-p-p62. Other derivatives showed potent Keap1-Nrf2 and Keap1-p-p62 PPI inhibitory activities, though the selectivity between the two activities was lower than K67.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sulfonamidas
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Proteínas de Ligação a RNA
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Proteínas Ativadoras de ras GTPase
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Fator 2 Relacionado a NF-E2
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Proteína 1 Associada a ECH Semelhante a Kelch
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Naftalenos
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1-Naftilamina
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article