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.
Keywords:
Keap1; Nrf2; Protein-protein interaction inhibitor; p62/Sqstm1.
Copyright © 2016 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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1-Naphthylamine / analogs & derivatives*
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1-Naphthylamine / chemical synthesis
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1-Naphthylamine / chemistry
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1-Naphthylamine / pharmacology
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Dose-Response Relationship, Drug
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Humans
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Kelch-Like ECH-Associated Protein 1 / antagonists & inhibitors*
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Kelch-Like ECH-Associated Protein 1 / chemistry
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Molecular Structure
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NF-E2-Related Factor 2 / antagonists & inhibitors*
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NF-E2-Related Factor 2 / chemistry
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Naphthalenes / chemistry
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Naphthalenes / pharmacology*
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Protein Binding / drug effects
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RNA-Binding Proteins / antagonists & inhibitors*
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RNA-Binding Proteins / chemistry
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / chemistry
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Sulfonamides / pharmacology*
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ras GTPase-Activating Proteins / antagonists & inhibitors*
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ras GTPase-Activating Proteins / chemistry
Substances
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2-acetonyl-1,4-bis((4-etoxybenzensulfonyl)amino)naphthalene
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KEAP1 protein, human
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Kelch-Like ECH-Associated Protein 1
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NF-E2-Related Factor 2
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Naphthalenes
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P62 protein, human
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RNA-Binding Proteins
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Sulfonamides
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ras GTPase-Activating Proteins
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naphthalene
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1-Naphthylamine