Challenges and Limitations of Targeting the Keap1-Nrf2 Pathway for Neurotherapeutics: Bach1 De-Repression to the Rescue.
BACH1
Kelch domain
Nrf2
displacement activator
ubiquitylation pathways
Journal
Frontiers in aging neuroscience
ISSN: 1663-4365
Titre abrégé: Front Aging Neurosci
Pays: Switzerland
ID NLM: 101525824
Informations de publication
Date de publication:
2021
2021
Historique:
received:
27
02
2021
accepted:
15
03
2021
entrez:
26
4
2021
pubmed:
27
4
2021
medline:
27
4
2021
Statut:
epublish
Résumé
The Keap1-Nrf2 signaling axis is a validated and promising target for cellular defense and survival pathways. This minireview discusses the potential off-target effects and their impact on future drug development originating from Keap1-targeting small molecules that function as displacement activators of the redox-sensitive transcription factor Nrf2. We argue that small-molecule displacement activators, similarly to electrophiles, will release both Nrf2 and other Keap1 client proteins from the ubiquitin ligase complex. This non-specificity is likely unavoidable and may result in off-target effects during Nrf2 activation by targeting Keap1. The small molecule displacement activators may also target Kelch domains in proteins other than Keap1, causing additional off-target effects unless designed to ensure specificity for the Kelch domain only in Keap1. A potentially promising and alternative therapeutic approach to overcome this non-specificity emerging from targeting Keap1 is to inhibit the Nrf2 repressor Bach1 for constitutive activation of the Nrf2 pathway and bypass the Keap1-Nrf2 complex.
Identifiants
pubmed: 33897412
doi: 10.3389/fnagi.2021.673205
pmc: PMC8060438
doi:
Types de publication
Journal Article
Review
Langues
eng
Pagination
673205Informations de copyright
Copyright © 2021 Hushpulian, Ammal Kaidery, Ahuja, Poloznikov, Sharma, Gazaryan and Thomas.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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