Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

Antonio Cuadrado; Ana I. Rojo; Geoffrey Wells; John Hayes; Sharon P. Cousin; William L. Rumsey; Otis C. Attucks; Stephen Franklin; Anna-Liisa Levonen; Thomas W. Kensler; Albena Dinkova-Kostova

doi:10.1038/s41573-018-0008-x

Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

Antonio Cuadrado, Ana I. Rojo, Geoffrey Wells, John Hayes, Sharon P. Cousin, William L. Rumsey, Otis C. Attucks, Stephen Franklin, Anna-Liisa Levonen, Thomas W. Kensler, Albena Dinkova-Kostova (Lead / Corresponding author)

Cellular Medicine

Research output: Contribution to journal › Review article › peer-review

423 Citations (Scopus)

324 Downloads (Pure)

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.

Original language	English
Pages (from-to)	295-317
Number of pages	23
Journal	Nature Reviews Drug Discovery
Volume	18
Issue number	4
Early online date	4 Jan 2019
DOIs	https://doi.org/10.1038/s41573-018-0008-x
Publication status	Published - Apr 2019

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10.1038/s41573-018-0008-x

Author Accepted ManuscriptAccepted author manuscript, 4.59 MB

Cite this

@article{3dfcfaaf63bc4907b7f420c0ffd469b4,

title = "Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases",

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.",

author = "Antonio Cuadrado and Rojo, {Ana I.} and Geoffrey Wells and John Hayes and Cousin, {Sharon P.} and Rumsey, {William L.} and Attucks, {Otis C.} and Stephen Franklin and Anna-Liisa Levonen and Kensler, {Thomas W.} and Albena Dinkova-Kostova",

note = "This work was supported by Grants SAF2015-71304-REDT, SAF2016-76520-R, of the Spanish Ministry of Economy and Competiveness; P_37_732/2016 REDBRAIN of the European Regional Development Fund; Competitiveness Operational Program 2014-2020; NIH grant R35 CA197222; Cancer Research UK grant C20953/A18644; Medical Research Council grant MR/N009851/1; Biotechnology and Biological Sciences Research Council grant BB/L01923X/1; Tenovus Scotland grant T17/14, grant 275147 from The Academy of Finland, Sigrid Juselius Foundation, Finnish Cancer Organizations.",

year = "2019",

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doi = "10.1038/s41573-018-0008-x",

language = "English",

volume = "18",

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Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. / Cuadrado, Antonio; Rojo, Ana I.; Wells, Geoffrey; Hayes, John; Cousin, Sharon P.; Rumsey, William L.; Attucks, Otis C.; Franklin, Stephen; Levonen, Anna-Liisa; Kensler, Thomas W.; Dinkova-Kostova, Albena (Lead / Corresponding author).

In: Nature Reviews Drug Discovery, Vol. 18, No. 4, 04.2019, p. 295-317.

Research output: Contribution to journal › Review article › peer-review

TY - JOUR

T1 - Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

AU - Cuadrado, Antonio

AU - Rojo, Ana I.

AU - Wells, Geoffrey

AU - Hayes, John

AU - Cousin, Sharon P.

AU - Rumsey, William L.

AU - Attucks, Otis C.

AU - Franklin, Stephen

AU - Levonen, Anna-Liisa

AU - Kensler, Thomas W.

AU - Dinkova-Kostova, Albena

N1 - This work was supported by Grants SAF2015-71304-REDT, SAF2016-76520-R, of the Spanish Ministry of Economy and Competiveness; P_37_732/2016 REDBRAIN of the European Regional Development Fund; Competitiveness Operational Program 2014-2020; NIH grant R35 CA197222; Cancer Research UK grant C20953/A18644; Medical Research Council grant MR/N009851/1; Biotechnology and Biological Sciences Research Council grant BB/L01923X/1; Tenovus Scotland grant T17/14, grant 275147 from The Academy of Finland, Sigrid Juselius Foundation, Finnish Cancer Organizations.

PY - 2019/4

Y1 - 2019/4

N2 - 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.

AB - 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.

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JF - Nature Reviews Drug Discovery

SN - 1474-1776

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Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

Abstract

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Contribution by NRF2 Upregulation to Lung Carcinogenesis and the Possible Therapeutic Value of NRF2 Inhibition by GSK-3 (Joint with Universities of St Andrews, Edinburgh and Pennsylvania)

The Role of the Keap1/Nrf2 Pathway in Tumour Metabolic Adaptation (Joint with University of Cambridge and University College London)

The Spatiotemporal Regulation of the Keap1/Nrf2 Pathway (Joint with University College London)

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Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

Abstract

UN SDGs

Access to Document

Other files and links

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Projects

Contribution by NRF2 Upregulation to Lung Carcinogenesis and the Possible Therapeutic Value of NRF2 Inhibition by GSK-3 (Joint with Universities of St Andrews, Edinburgh and Pennsylvania)

The Role of the Keap1/Nrf2 Pathway in Tumour Metabolic Adaptation (Joint with University of Cambridge and University College London)

The Spatiotemporal Regulation of the Keap1/Nrf2 Pathway (Joint with University College London)

Cite this