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 journalReview article

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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 languageEnglish
Pages (from-to)295-317
Number of pages23
JournalNature Reviews Drug Discovery
Volume18
Issue number4
Early online date4 Jan 2019
DOIs
Publication statusPublished - Apr 2019

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Chronic Disease
NF-E2-Related Factor 2
Ubiquitin-Protein Ligases
Cytoprotection
Neurodegenerative Diseases
Oxidation-Reduction
Cysteine
Homeostasis
Transcription Factors
Maintenance
Pathology
Inflammation
Safety
Lung
Liver
Therapeutics
Neoplasms
Proteins
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 ; Vol. 18, No. 4. pp. 295-317.
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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.",
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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, vol. 18, no. 4, pp. 295-317. https://doi.org/10.1038/s41573-018-0008-x

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 journalReview article

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

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AU - Rojo, Ana I.

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AU - Dinkova-Kostova, Albena

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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.

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