Abstract: This mini-review presents the authors’ vision on the current status and future trends in the development of neuroprotective agents working via activation of nuclear factor erythroid 2-related factor 2 (Nrf2), and in particular, via disruption of Nrf2-Keap1 interaction. Tere are two opposite “chemical” mechanisms underlying such activation: the frst one is a non-specifc covalent modifcation of Keap1 thiols, resulting in side e?ects of varied severity, and the second one is the shif 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 sufcient biological activity in comparison with common Nrf2 activators working via Keap1 thiol modifcation. 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). Te commercially 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 efciency of Nrf2 activation.

Key words: Nrf2, Keap1, Bach1, electrophiles, oxidative stress, antioxidants