The status of Nrf2-based therapeutics：current perspectives and future prospects

Irina G Gazaryan; Bobby Thomas

doi:10.4103/1673-5374.194706

摘要：hTis mini-review presents the authors’ vision on the current status and future trends in the development of neuroprotective agents workingvia activation of nuclear factor erythroid 2-related factor 2 (Nrf2), and in particular,via disruption of Nrf2-Keap1 interaction. There are two opposite “chemical” mechanisms under-lying such activation: the ifrst one is a non-speciifc covalent modiifcation of Keap1 thiols, resulting in side effects of varied severity, and the second one is the shitf of the Nrf2-Kelch-like ECH associated protein-1 (Keap1) binding equilibrium in the presence of a competitive and chemically benign displacement agent. At this point, no displacement activators exhibit suffcient biological activity in comparison with common Nrf2 activators workingvia Keap1 thiol modiifcation. Hence, the hope in therapeutics is now linked to the FDA approved dimethylfumarate, whose derivative, monomethylfumarate, as we demonstrated recently, is much less toxic but equally biologically potent and an ideal candidate for clinical trials right now. A newly emerging player is a nuclear inhibitor of Nrf2, BTB domain and CNC homolog 1 (Bach1). The commer-cially developed Bach1 inhibitors are currently under investigation in our laboratory showing promising results. In our viewpoint, the perfect future drug will present the combination of a displacement activator and Bach1 inhibitor to insure safety and effciency of Nrf2 activation.