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Nat Rev Drug Discov. 2019 Jan 4. doi: 10.1038/s41573-018-0008-x. [Epub ahead of print]

Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases.

Author information

1
Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry and Instituto de Investigaciones Biomédicas Alberto Sols UAM-CSIC, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain.
2
Victor Babes National Institute of Pathology, Bucharest, Romania.
3
UCL School of Pharmacy, University College London, London, UK.
4
Jacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee, Scotland, UK.
5
Reata Pharmaceuticals, Irving, TX, USA.
6
GlaxoSmithKline, Collegeville, PA, USA.
7
vTv Therapeutics, High Point, NC, USA.
8
Evgen Pharma, Wilmslow, Cheshire, UK.
9
A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
10
Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
11
Jacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee, Scotland, UK. a.dinkovakostova@dundee.ac.uk.
12
Department of Pharmacology and Molecular Sciences and Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. a.dinkovakostova@dundee.ac.uk.

Abstract

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.

PMID:
30610225
DOI:
10.1038/s41573-018-0008-x

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