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)

Research output: Contribution to journal › Article

Abstract

Transcription factor NF-E2 p45-related factor 2 (NRF2, gene name NFE2L2) and its principal negative regulator, the E3 ligase adapter Kelch-like ECH-associated protein 1 (KEAP1), play a critical role in the development and progression of chronic diseases of the lung and liver, autoimmune, neurodegenerative and metabolic disorders, and also cancer. NRF2 activation provides cytoprotection against numerous pathologies characterized by chronic inflammation, metabolic alterations and redox disturbances. 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.
LanguageEnglish
Pages1-23
Number of pages23
JournalNature Reviews Drug Discovery
Publication statusPublished - 4 Jan 2019

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Chronic Disease
NF-E2-Related Factor 2
Ubiquitin-Protein Ligases
Cytoprotection
Neurodegenerative Diseases
Oxidation-Reduction
Names
Cysteine
Transcription Factors
Pathology
Inflammation
Safety
Lung
Liver
Therapeutics
Genes
Neoplasms
Kelch-Like ECH-Associated Protein 1

Cite this

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. / Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. In: Nature Reviews Drug Discovery. 2019 ; pp. 1-23.
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title = "Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases",
abstract = "Transcription factor NF-E2 p45-related factor 2 (NRF2, gene name NFE2L2) and its principal negative regulator, the E3 ligase adapter Kelch-like ECH-associated protein 1 (KEAP1), play a critical role in the development and progression of chronic diseases of the lung and liver, autoimmune, neurodegenerative and metabolic disorders, and also cancer. NRF2 activation provides cytoprotection against numerous pathologies characterized by chronic inflammation, metabolic alterations and redox disturbances. 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.",
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Cuadrado, A, Rojo, AI, Wells, G, Hayes, J, Cousin, SP, Rumsey, WL, Attucks, OC, Franklin, S, Levonen, A-L, Kensler, TW & Dinkova-Kostova, A 2019, 'Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases', Nature Reviews Drug Discovery, pp. 1-23.

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, 04.01.2019, p. 1-23.

Research output: Contribution to journal › Article

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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

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AU - Rumsey, William L.

AU - Attucks, Otis C.

AU - Franklin, Stephen

AU - Levonen, Anna-Liisa

AU - Kensler, Thomas W.

AU - Dinkova-Kostova, Albena

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PY - 2019/1/4

Y1 - 2019/1/4

N2 - Transcription factor NF-E2 p45-related factor 2 (NRF2, gene name NFE2L2) and its principal negative regulator, the E3 ligase adapter Kelch-like ECH-associated protein 1 (KEAP1), play a critical role in the development and progression of chronic diseases of the lung and liver, autoimmune, neurodegenerative and metabolic disorders, and also cancer. NRF2 activation provides cytoprotection against numerous pathologies characterized by chronic inflammation, metabolic alterations and redox disturbances. 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 - Transcription factor NF-E2 p45-related factor 2 (NRF2, gene name NFE2L2) and its principal negative regulator, the E3 ligase adapter Kelch-like ECH-associated protein 1 (KEAP1), play a critical role in the development and progression of chronic diseases of the lung and liver, autoimmune, neurodegenerative and metabolic disorders, and also cancer. NRF2 activation provides cytoprotection against numerous pathologies characterized by chronic inflammation, metabolic alterations and redox disturbances. 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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Cuadrado A, Rojo AI, Wells G, Hayes J, Cousin SP, Rumsey WL et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nature Reviews Drug Discovery. 2019 Jan 4;1-23.