Design, Synthesis, and Evaluation of Triazole Derivatives That Induce Nrf2 Dependent Gene Products and Inhibit the Keap1-Nrf2 Protein-Protein Interaction

被引：93

作者：

Bertrand, Helene C. ^{[1
]}

Schaap, Marjolein ^{[1
]}

Baird, Liam ^{[2
]}

Georgakopoulos, Nikolaos D. ^{[1
]}

Fowkes, Adrian ^{[1
]}

Thiollier, Clarisse ^{[1
]}

Kachi, Hiroko ^{[1
]}

Dinkova-Kostova, Albena T. ^{[2
,3
,4
]}

Wells, Geoff ^{[1
]}

机构：

[1] UCL, UCL Sch Pharm, London WC1N 1AX, England

[2] Univ Dundee, Med Res Inst, Div Canc Res, Jacqui Wood Canc Ctr, Dundee DD1 9SY, Scotland

[3] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA

[4] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 18期

基金：

英国生物技术与生命科学研究理事会;

关键词：

RANDOMIZED CLINICAL-TRIAL; OXIDATIVE STRESS; PEPTIDE INHIBITORS; NRF2-KEAP1; COMPLEX; KELCH DOMAIN; DLG MOTIFS; BINDING; PATHWAY; UBIQUITINATION; DISCOVERY;

D O I：

10.1021/acs.jmedchem.5b00602

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The transcription factor Nrf2 regulates the expression of a large network of cytoprotective and metabolic enzymes and proteins. Compounds that directly and reversibly inhibit the interaction between Nrf2 and its main negative regulator Keap1 are potential pharmacological agents for a range of disease types including neurodegenerative conditions and cancer. We describe the development of a series of 1,4-dipheny1-1,2,3-triazole compounds that inhibit the Nrf2-Keap1 protein protein interaction (PPI) in vitro and in live cells and up-regulate the expression of Nrf2-dependent gene products.

引用

页码：7186 / 7194

页数：9

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