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)

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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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Cuadrado, A., Rojo, A. I., Wells, G., Hayes, J., Cousin, S. P., Rumsey, W. L., Attucks, O. C., Franklin, S., Levonen, A-L., Kensler, T. W., & Dinkova-Kostova, A. (2019). Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nature Reviews Drug Discovery, 18(4), 295-317. https://doi.org/10.1038/s41573-018-0008-x