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

被引：95
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
相关论文
共 47 条
[1]   New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays [J].
Baell, Jonathan B. ;
Holloway, Georgina A. .
JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (07) :2719-2740
[2]   Monitoring Keap1-Nrf2 interactions in single live cells [J].
Baird, Liam ;
Swift, Sam ;
Lleres, David ;
Dinkova-Kostova, Albena T. .
BIOTECHNOLOGY ADVANCES, 2014, 32 (06) :1133-1144
[3]   Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex [J].
Baird, Liam ;
Lleres, David ;
Swift, Sam ;
Dinkova-Kostova, Albena T. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2013, 110 (38) :15259-15264
[4]   The cytoprotective role of the Keap1-Nrf2 pathway [J].
Baird, Liam ;
Dinkova-Kostova, Albena T. .
ARCHIVES OF TOXICOLOGY, 2011, 85 (04) :241-272
[5]   Evaluation of DOCK 6 as a pose generation and database enrichment tool [J].
Brozell, Scott R. ;
Mukherjee, Sudipto ;
Balius, Trent E. ;
Roe, Daniel R. ;
Case, David A. ;
Rizzo, Robert C. .
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 2012, 26 (06) :749-773
[6]   Kinetic Analyses of Keap1-Nrf2 Interaction and Determination of the Minimal Nrf2 Peptide Sequence Required for Keap1 Binding Using Surface Plasmon Resonance [J].
Chen, Yu ;
Inoyama, Daigo ;
Ah-Ng Tony Kong ;
Beamer, Lesa J. ;
Hu, Longqin .
CHEMICAL BIOLOGY & DRUG DESIGN, 2011, 78 (06) :1014-1021
[7]   Impaired Redox Signaling and Antioxidant Gene Expression in Endothelial Cells in Diabetes: A Role for Mitochondria and the Nuclear Factor-E2-Related Factor 2-Kelch-Like ECH-Associated Protein 1 Defense Pathway [J].
Cheng, Xinghua ;
Siow, Richard C. M. ;
Mann, Giovanni E. .
ANTIOXIDANTS & REDOX SIGNALING, 2011, 14 (03) :469-487
[8]   Preclinical and clinical evaluation of sulforaphane for chemoprevention in the breast [J].
Cornblatt, Brian S. ;
Ye, Lingxiang ;
Dinkova-Kostova, Albena T. ;
Erb, Melanie ;
Fahey, Jed W. ;
Singh, Navin K. ;
Chen, Min-Shue A. ;
Stierer, Tracey ;
Garrett-Mayer, Elizabeth ;
Argani, Pedram ;
Davidson, Nancy E. ;
Talalay, Paul ;
Kensler, Thomas W. ;
Visvanathan, Kala .
CARCINOGENESIS, 2007, 28 (07) :1485-1490
[9]  
Dinikova-Kostova AT, 2004, METHOD ENZYMOL, V382, P423
[10]   Chemoprotection Against Cancer by Isothiocyanates: A Focus on the Animal Models and the Protective Mechanisms [J].
Dinkova-Kostova, Albena T. .
NATURAL PRODUCTS IN CANCER PREVENTION AND THERAPY, 2013, 329 :179-201
12345