Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

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.
This work was supported by grants SAF2015-71304-REDT and SAF2016-76520-R from the Spanish Ministry Economy and Competitiveness; P_37_732/2016 REDBRAIN from the European Regional Development Fund; Competitiveness Operational Program 2014–2020; US National Institutes of Health 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; and grant 275147 from the Academy of Finland, Sigrid Juselius Foundation and Finnish Cancer Foundation.