Challenges and Limitations of Targeting the Keap1-Nrf2 Pathway for Neurotherapeutics: Bach1 De-Repression to the Rescue

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 activato...

Full description

Bibliographic Details
Main Authors: Dmitry M. Hushpulian, Navneet Ammal Kaidery, Manuj Ahuja, Andrey A. Poloznikov, Sudarshana M. Sharma, Irina G. Gazaryan, Bobby Thomas
Format: Article
Language:English
Published: Frontiers Media S.A. 2021-04-01
Series:Frontiers in Aging Neuroscience
Subjects:
Online Access:https://www.frontiersin.org/articles/10.3389/fnagi.2021.673205/full
id doaj-54d2b73ecbdc47da83d47b5c45340714
record_format Article
spelling doaj-54d2b73ecbdc47da83d47b5c453407142021-04-08T04:15:28ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652021-04-011310.3389/fnagi.2021.673205673205Challenges and Limitations of Targeting the Keap1-Nrf2 Pathway for Neurotherapeutics: Bach1 De-Repression to the RescueDmitry M. Hushpulian0Dmitry M. Hushpulian1Navneet Ammal Kaidery2Navneet Ammal Kaidery3Manuj Ahuja4Manuj Ahuja5Manuj Ahuja6Andrey A. Poloznikov7Sudarshana M. Sharma8Irina G. Gazaryan9Irina G. Gazaryan10Irina G. Gazaryan11Irina G. Gazaryan12Bobby Thomas13Bobby Thomas14Bobby Thomas15Bobby Thomas16P. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, RussiaFaculty of Biology and Biotechnologies, Higher School of Economics, Moscow, RussiaDarby Children’s Research Institute, Medical University of South Carolina, Charleston, SC, United StatesDepartment of Pediatrics, Medical University of South Carolina, Charleston, SC, United StatesDarby Children’s Research Institute, Medical University of South Carolina, Charleston, SC, United StatesDepartment of Pediatrics, Medical University of South Carolina, Charleston, SC, United StatesDepartment of Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, United StatesFaculty of Biology and Biotechnologies, Higher School of Economics, Moscow, RussiaHollings Cancer Center, Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, United StatesP. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, RussiaFaculty of Biology and Biotechnologies, Higher School of Economics, Moscow, RussiaDepartment of Chemical Enzymology, M.V. Lomonosov Moscow State University, Moscow, RussiaDepartment of Chemistry and Physical Sciences, Dyson College of Arts and Sciences, Pace University, Pleasantville, NY, United StatesDarby Children’s Research Institute, Medical University of South Carolina, Charleston, SC, United StatesDepartment of Pediatrics, Medical University of South Carolina, Charleston, SC, United StatesDepartment of Neuroscience, Medical University of South Carolina, Charleston, SC, United States0Department of Drug Discovery, Medical University of South Carolina, Charleston, SC, United StatesThe 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.https://www.frontiersin.org/articles/10.3389/fnagi.2021.673205/fullNrf2Kelch domaindisplacement activatorubiquitylation pathwaysBACH1
collection DOAJ
language English
format Article
sources DOAJ
author Dmitry M. Hushpulian
Dmitry M. Hushpulian
Navneet Ammal Kaidery
Navneet Ammal Kaidery
Manuj Ahuja
Manuj Ahuja
Manuj Ahuja
Andrey A. Poloznikov
Sudarshana M. Sharma
Irina G. Gazaryan
Irina G. Gazaryan
Irina G. Gazaryan
Irina G. Gazaryan
Bobby Thomas
Bobby Thomas
Bobby Thomas
Bobby Thomas
spellingShingle Dmitry M. Hushpulian
Dmitry M. Hushpulian
Navneet Ammal Kaidery
Navneet Ammal Kaidery
Manuj Ahuja
Manuj Ahuja
Manuj Ahuja
Andrey A. Poloznikov
Sudarshana M. Sharma
Irina G. Gazaryan
Irina G. Gazaryan
Irina G. Gazaryan
Irina G. Gazaryan
Bobby Thomas
Bobby Thomas
Bobby Thomas
Bobby Thomas
Challenges and Limitations of Targeting the Keap1-Nrf2 Pathway for Neurotherapeutics: Bach1 De-Repression to the Rescue
Frontiers in Aging Neuroscience
Nrf2
Kelch domain
displacement activator
ubiquitylation pathways
BACH1
author_facet Dmitry M. Hushpulian
Dmitry M. Hushpulian
Navneet Ammal Kaidery
Navneet Ammal Kaidery
Manuj Ahuja
Manuj Ahuja
Manuj Ahuja
Andrey A. Poloznikov
Sudarshana M. Sharma
Irina G. Gazaryan
Irina G. Gazaryan
Irina G. Gazaryan
Irina G. Gazaryan
Bobby Thomas
Bobby Thomas
Bobby Thomas
Bobby Thomas
author_sort Dmitry M. Hushpulian
title Challenges and Limitations of Targeting the Keap1-Nrf2 Pathway for Neurotherapeutics: Bach1 De-Repression to the Rescue
title_short Challenges and Limitations of Targeting the Keap1-Nrf2 Pathway for Neurotherapeutics: Bach1 De-Repression to the Rescue
title_full Challenges and Limitations of Targeting the Keap1-Nrf2 Pathway for Neurotherapeutics: Bach1 De-Repression to the Rescue
title_fullStr Challenges and Limitations of Targeting the Keap1-Nrf2 Pathway for Neurotherapeutics: Bach1 De-Repression to the Rescue
title_full_unstemmed Challenges and Limitations of Targeting the Keap1-Nrf2 Pathway for Neurotherapeutics: Bach1 De-Repression to the Rescue
title_sort challenges and limitations of targeting the keap1-nrf2 pathway for neurotherapeutics: bach1 de-repression to the rescue
publisher Frontiers Media S.A.
series Frontiers in Aging Neuroscience
issn 1663-4365
publishDate 2021-04-01
description 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.
topic Nrf2
Kelch domain
displacement activator
ubiquitylation pathways
BACH1
url https://www.frontiersin.org/articles/10.3389/fnagi.2021.673205/full
work_keys_str_mv AT dmitrymhushpulian challengesandlimitationsoftargetingthekeap1nrf2pathwayforneurotherapeuticsbach1derepressiontotherescue
AT dmitrymhushpulian challengesandlimitationsoftargetingthekeap1nrf2pathwayforneurotherapeuticsbach1derepressiontotherescue
AT navneetammalkaidery challengesandlimitationsoftargetingthekeap1nrf2pathwayforneurotherapeuticsbach1derepressiontotherescue
AT navneetammalkaidery challengesandlimitationsoftargetingthekeap1nrf2pathwayforneurotherapeuticsbach1derepressiontotherescue
AT manujahuja challengesandlimitationsoftargetingthekeap1nrf2pathwayforneurotherapeuticsbach1derepressiontotherescue
AT manujahuja challengesandlimitationsoftargetingthekeap1nrf2pathwayforneurotherapeuticsbach1derepressiontotherescue
AT manujahuja challengesandlimitationsoftargetingthekeap1nrf2pathwayforneurotherapeuticsbach1derepressiontotherescue
AT andreyapoloznikov challengesandlimitationsoftargetingthekeap1nrf2pathwayforneurotherapeuticsbach1derepressiontotherescue
AT sudarshanamsharma challengesandlimitationsoftargetingthekeap1nrf2pathwayforneurotherapeuticsbach1derepressiontotherescue
AT irinaggazaryan challengesandlimitationsoftargetingthekeap1nrf2pathwayforneurotherapeuticsbach1derepressiontotherescue
AT irinaggazaryan challengesandlimitationsoftargetingthekeap1nrf2pathwayforneurotherapeuticsbach1derepressiontotherescue
AT irinaggazaryan challengesandlimitationsoftargetingthekeap1nrf2pathwayforneurotherapeuticsbach1derepressiontotherescue
AT irinaggazaryan challengesandlimitationsoftargetingthekeap1nrf2pathwayforneurotherapeuticsbach1derepressiontotherescue
AT bobbythomas challengesandlimitationsoftargetingthekeap1nrf2pathwayforneurotherapeuticsbach1derepressiontotherescue
AT bobbythomas challengesandlimitationsoftargetingthekeap1nrf2pathwayforneurotherapeuticsbach1derepressiontotherescue
AT bobbythomas challengesandlimitationsoftargetingthekeap1nrf2pathwayforneurotherapeuticsbach1derepressiontotherescue
AT bobbythomas challengesandlimitationsoftargetingthekeap1nrf2pathwayforneurotherapeuticsbach1derepressiontotherescue
_version_ 1721535499808538624