Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

Subjects

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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Fig. 1: Regulation of NRF2 by KEAP1 and its pharmacological targeting.
Fig. 2: Expression of KEAP1 and NFE2L2 mRNAs in human brain and blood.
Fig. 3: Crystal structure of KEAP1 domains.
Fig. 4: Modulation of cancer risk according to status of NRF2.

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Acknowledgements

This work was supported by grants SAF2015-71304-REDT and SAF2016-76520-R from the Spanish Ministry of 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.

Competing interests

S.P.C. is employed by Reata Pharmaceuticals. O.C.A. is employed by vTv Therapeutics. W.L.R. is employed by GlaxoSmithKline. S.F. is Company Director as well as an employee and minority shareholder in Evgen Pharma. A.T.D.-K. is a member of the scientific advisory board for Evgen Pharma.

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Correspondence to Albena T. Dinkova-Kostova.

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RCSB Protein Data Bank: https://www.rcsb.org/

Statistical software package ‘R’: http://www.r-project.org

Glossary

Antioxidant response element

(ARE). Specific DNA sequences that are present in the promoter regions of transcription factor NF-E2 p45-related factor 2 (NRF2)-target genes. The ARE was discovered before NRF2, and its name originates from the fact that it was first identified in the promoter regions of genes that are induced by phenolic antioxidants.

Xenobiotic biotransformation

The metabolic conversion of exogenous chemicals into water-soluble compounds to facilitate excretion, primarily via urine or bile.

Redox stress

An imbalance between oxidants and antioxidants in favour of the oxidants, leading to a disruption of redox signalling and control and/or molecular damage.

Electrophiles

Electron-deficient atoms or molecules that take an electron pair from a donor molecule to form a covalent bond.

Gluconeogenesis

Metabolic process that generates glucose from non-carbohydrate carbon substrates, such as lactate, glycerol and glucogenic amino acids.

Proteostasis

Protein homeostasis.

Autophagosome

A spherical double-layer membrane structure within the cell. The autophagosome is the key structure in macroautophagy, a type of intracellular degradation process.

Interferonopathies

Mendelian disorders associated with upregulation of interferon.

Chronic obstructive pulmonary disease

(COPD). Progressive lung disease including emphysema, chronic bronchitis and refractory (non-reversible) asthma.

Emphysema

Progressive lung disease that causes shortness of breath owing to overinflation of the alveoli.

Clara cells

Dome-shaped cells found in the bronchioles of the lungs.

Alport syndrome

Genetic disorder of the glomerular basement membrane, part of the glomerular filtration unit, characterized by kidney disease, hearing loss and eye abnormalities.

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Cuadrado, A., Rojo, A.I., Wells, G. et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Discov 18, 295–317 (2019). https://doi.org/10.1038/s41573-018-0008-x

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