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Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development

Robledinos-Antón, Natalia, Fernández-Ginés, Raquel, Manda, Gina, Cuadrado, Antonio·2019·Oxidative Medicine and Cellular Longevity
DOI 10.1155/2019/9372182PMC PMC6664516
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Abstract

The transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) triggers the first line of homeostatic responses against a plethora of environmental or endogenous deviations in redox metabolism, proteostasis, inflammation, etc. Therefore, pharmacological activation of NRF2 is a promising therapeutic approach for several chronic diseases that are underlined by oxidative stress and inflammation, such as neurodegenerative, cardiovascular, and metabolic diseases. A particular case is cancer, where NRF2 confers a survival advantage to constituted tumors, and therefore, NRF2 inhibition is desired. This review describes the electrophilic and nonelectrophilic NRF2 activators with clinical projection in various chronic diseases. We also analyze the status of NRF2 inhibitors, which at this time provide proof of concept for blocking NRF2 activity in cancer therapy.

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Figure 1 Domain structures of NRF2 and KEAP1. (a) Domain structure of NRF2. NRF2 possesses six highly conserved domains called NRF2-ECH homology (Neh) domains [167]. The functional role of each Neh domain is specified. Within the Neh2 domain, the low-affinity (DLG) and high-affinity (ETGE) binding domains to KEAP1 are zoomed in. (b) Domain structure of a KEAP1 monomer showing the position of cysteine residues. The N-terminal BTB (bric-a-brac, tramtrack, broad complex) domain participates in homodimerization and binding to CUL3/RBX1. The C-terminal region, DGR (double glycine repeat) domain, contains a double glycine repeat called Kelch repeat that binds NRF2-Neh2 domain. The intervening region (IVR/LR) connects BTB and DGR domains and is particularly rich in redox-sensitive cysteine residues. Red and blue cysteine residues in KEAP1 are the most relevant for electrophile reactivity. This figure has been modified and extended from [168] to highlight the degradation domains in NRF2 and the cysteines of KEAP1.
Figure 1 Domain structures of NRF2 and KEAP1. (a) Domain structure of NRF2. NRF2 possesses six highly conserved domains called NRF2-ECH homology (Neh) domains [167]. The functional role of each Neh domain is specified. Within the Neh2 domain, the low-affinity (DLG) and high-affinity (ETGE) binding domains to KEAP1 are zoomed in. (b) Domain structure of a KEAP1 monomer showing the position of cysteine residues. The N-terminal BTB (bric-a-brac, tramtrack, broad complex) domain participates in homodimerization and binding to CUL3/RBX1. The C-terminal region, DGR (double glycine repeat) domain, contains a double glycine repeat called Kelch repeat that binds NRF2-Neh2 domain. The intervening region (IVR/LR) connects BTB and DGR domains and is particularly rich in redox-sensitive cysteine residues. Red and blue cysteine residues in KEAP1 are the most relevant for electrophile reactivity. This figure has been modified and extended from [168] to highlight the degradation domains in NRF2 and the cysteines of KEAP1.CC BY · PubMed Central
Figure 2 Summary of the pharmacological strategies to modulate NRF2 activity.
Figure 2 Summary of the pharmacological strategies to modulate NRF2 activity.CC BY · PubMed Central

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Metadata

Authors
Robledinos-Antón, N., Fernández-Ginés, R., Manda, G., & Cuadrado, A.
Affiliations
  • Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz) and Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain
  • Victor Babes National Institute of Pathology, Bucharest, Romania
ORCID
Venue
Oxidative Medicine and Cellular Longevity
Publisher
Wiley
Published
2019-07-14
Volume
2019
Pages
1-20
ISSN
  • 1942-0900
  • 1942-0994
DOI
10.1155/2019/9372182
PMC
PMC6664516
Cited by
413
References
16
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (unspecified)
Funders
  • European Regional Development Fund (P_37_732/2016, B2017/BMD-3827, SAF2016-76520-R)
  • Autonomous Community of Madrid (P_37_732/2016, B2017/BMD-3827, SAF2016-76520-R)
  • Ministerio de Economía y Competitividad (P_37_732/2016, B2017/BMD-3827, SAF2016-76520-R)

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