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

Hushpulian, D.M.; Kaidery, N.A.; Ahuja, M.; Poloznikov, A.A.; Sharma, S.M.; Gazaryan, I.G.; Thomas, B.

Авторы: Hushpulian Dmitry M., Kaidery Navneet Ammal, Ahuja Manuj, Poloznikov Andrey A., Sharma Sudarshana M., Gazaryan Irina G., Thomas Bobby
Журнал: Frontiers in aging neuroscience
Том: 13
Год издания: 2021
Издательство: Frontiers Research Foundation
Местоположение издательства: Switzerland
Номер статьи: 13:673205
DOI: 10.3389/fnagi.2021.673205
Аннотация: 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.
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