Therapeutic targeting of the NRF2 and KEAP 1 partnership in chronic diseases

被引：1214

作者：

Cuadrado, Antonio ^{[1
,2
,3
]}

Rojo, Ana, I ^{[1
,2
]}

Wells, Geoffrey ^{[4
]}

Hayes, John D. ^{[5
]}

Cousins, Sharon P. ^{[6
]}

Rumsey, William L. ^{[7
]}

Attucks, Otis C. ^{[8
]}

Franklin, Stephen ^{[9
]}

Levonen, Anna-Liisa ^{[10
]}

Kensler, Thomas W. ^{[11
]}

Dinkova-Kostova, Albena T. ^{[5
,12
,13
]}

机构：

[1] Autonomous Univ Madrid, Fac Med, Dept Biochem, Inst Invest Sanitaria Paz Idi Paz,Ctr Invest Biom, Madrid, Spain

[2] Autonomous Univ Madrid, Fac Med, Inst Invest Biomed Alberto Sols UAM CSIC, Madrid, Spain

[3] Victor Babes Natl Inst Pathol, Bucharest, Romania

[4] UCL, UCL Sch Pharm, London, England

[5] Univ Dundee, Sch Med, Div Cellular Med, Jacqui Wood Canc Ctr, Dundee, Scotland

[6] Reata Pharmaceut, Irving, TX USA

[7] GlaxoSmithKline, Collegeville, PA USA

[8] vTv Therapeut, High Point, NC USA

[9] Evgen Pharma, Wilmslow, Cheshire, England

[10] Univ Eastern Finland, AI Virtanen Inst Mol Sci, Kuopio, Finland

[11] Fred Hutchinson Canc Res Ctr, Translat Res Program, 1124 Columbia St, Seattle, WA 98104 USA

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

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

来源：

NATURE REVIEWS DRUG DISCOVERY | 2019年 / 18卷 / 04期

基金：

美国国家卫生研究院; 芬兰科学院; 英国医学研究理事会; 英国生物技术与生命科学研究理事会;

关键词：

TRANSCRIPTION FACTOR NRF2; NF-KAPPA-B; PROTEIN-PROTEIN INTERACTION; SMOKE-INDUCED EMPHYSEMA; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ANTIOXIDANT RESPONSE ELEMENT; REMITTING MULTIPLE-SCLEROSIS; GENE PROMOTER POLYMORPHISM; FRATAXIN DEFICIENCY LEADS; RELEASE DIMETHYL FUMARATE;

D O I：

10.1038/s41573-018-0008-x

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 [微生物学]; 090105 [作物生产系统与生态工程];

摘要：

The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (KEAP1), are critical in the maintenance of redox, metabolic and protein homeostasis, as well as the regulation of inflammation. Thus, NRF2 activation provides cytoprotection against numerous pathologies including chronic diseases of the lung and liver; autoimmune, neurodegenerative and metabolic disorders; and cancer initiation. One NRF2 activator has received clinical approval and several electrophilic modifiers of the cysteine-based sensor KEAP1 and inhibitors of its interaction with NRF2 are now in clinical development. However, challenges regarding target specificity, pharmacodynamic properties, efficacy and safety remain.

引用

页码：295 / 317

页数：23

共 328 条

[1]

Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich's Ataxia Models [J].