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Perspectives on the Clinical Development of NRF2-Targeting Drugs

Part of the Handbook of Experimental Pharmacology book series (HEP,volume 264)

Abstract

The transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) triggers homeostatic responses against a plethora of environmental or endogenous deviations in redox metabolism, inflammation, proteostasis, etc. Therefore, pharmacological activation of NRF2 is a promising therapeutic strategy for several chronic diseases that are underlined by low-grade oxidative inflammation and dysregulation of redox metabolism, such as neurodegenerative, cardiovascular, and metabolic diseases. While NRF2 activation is useful in inhibiting carcinogenesis, its inhibition is needed in constituted tumors where NRF2 provides a survival advantage in the challenging tumor niche. This review describes the electrophilic and non-electrophilic NRF2 activators with clinical projection in various chronic diseases. We also analyze the status of NRF2 inhibitors, which are for the moment in a proof-of-concept stage. Advanced in silico screening and medicinal chemistry are expected to provide new or repurposing small molecules with increased potential for fostering the development of targeted NRF2 modulators.

Graphical Abstract

The nuclear factor erythroid 2 (NFE2)-related factor 2 (NRF2) is rapidly degraded by proteasomes under a basal condition in a Keap1-dependent manner. ROS oxidatively modifies Keap1 to release NRF2 and allow its nuclear translocation. Here it binds to the antioxidant response element to regulate gene transcription. An alternative mechanism controlling NRF2 stability is glycogen synthase kinase 3 (GSK-3)-induced phosphorylation. Indicated in blue are NRF2-activating and NRF2-inhibiting drugs.

Keywords

  • Chronic diseases
  • Cytoprotection
  • Inflammation

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Fig. 1
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Fig. 3

Abbreviations

AD:

Alzheimer’s disease

AHR:

Aryl hydrocarbon receptor

BACH1:

BTB domain and CNC homolog 1

BTB:

Broad complex, tramtrack, bric-a-brac

CUL3:

Cullin 3

DMF:

Dimethyl fumarate

DRG:

Double glycine repeat

GSH:

Glutathione

GSK-3:

Glycogen synthase kinase

IVR:

Intervening region

KEAP1:

Kelch-like ECH-associated protein 1

MMF:

Monomethyl fumarate

MS:

Multiple sclerosis

NFE2L2 :

Gene encoding NRF2

NRF2:

Nuclear factor erythroid 2-related factor 2

PD:

Parkinson’s disease

PPI:

Protein-protein interaction

RBX1:

RING-box protein 1

ROS:

Reactive oxygen species

SFN:

Sulforaphane

SQSTM1:

Sequestosome 1

XRE:

Xenobiotic response element

β-TrCP:

Beta-transducin repeat containing E3 ubiquitin protein ligase

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Acknowledgements

This work was supported by grants SAF2016-76520-R of the Spanish Ministry of Economy and Competitiveness, B2017/BMD-3827 of the Autonomous Community of Madrid, and P_37_732/2016 REDBRAIN of the European Regional Development Fund, Competitiveness Operational Program 2014–2020. RFG and DL are recipient of FPI and FPU contracts, respectively, of the Spanish Ministry of Economy and Competitiveness.

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The authors declare that there is no conflict of interest regarding the publication of this paper.

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Lastra, D., Fernández-Ginés, R., Manda, G., Cuadrado, A. (2020). Perspectives on the Clinical Development of NRF2-Targeting Drugs. In: Schmidt, H.H.H.W., Ghezzi, P., Cuadrado, A. (eds) Reactive Oxygen Species . Handbook of Experimental Pharmacology, vol 264. Springer, Cham. https://doi.org/10.1007/164_2020_381

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