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 |
|---|---|
| Number of pages | 23 |
| Journal | Nature Reviews Drug Discovery |
| Early online date | 4 Jan 2019 |
| DOIs | |
| Publication status | E-pub ahead of print - 4 Jan 2019 |
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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, 04.01.2019.Research output: Contribution to journal › Article
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 - 2019/1/4
Y1 - 2019/1/4
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.
UR - http://www.scopus.com/inward/record.url?scp=85059555270&partnerID=8YFLogxK
U2 - 10.1038/s41573-018-0008-x
DO - 10.1038/s41573-018-0008-x
M3 - Article
JO - Nature Reviews Drug Discovery
JF - Nature Reviews Drug Discovery
SN - 1474-1776
ER -