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 articlepeer-review

    850 Citations (Scopus)
    919 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 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

    ASJC Scopus subject areas

    • Pharmacology
    • Drug Discovery

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