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
收藏
页码：7186 / 7194
页数：9
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