The transcription factor Nrf2 regulates large networks of proteins that protect against damage by oxidants, electrophiles, and pro-inflammatory agents, allowing adaptation and survival under conditions of stress. Pharmacological activation of Nrf2 with small molecules (termed inducers) holds promise as a potential strategy for the prevention and treatment of chronic disease. Many inducers, such as the isothiocyanates and cyanoenones, are electrophiles and activate Nrf2 by targeting discreet highly reactive sensor cysteines within Kelch-like ECH-associated protein 1 (Keap1), the main negative regulator of Nrf2. At low concentrations, representatives of these two inducer classes chemically modify C151 in Keap1 impairing its repressor function, and allowing for Nrf2 accumulation and enhanced transcription of its target genes. However, at higher inducer concentrations, Nrf2 accumulation proceeds in the absence of C151, albeit at a lower magnitude. This flexibility in the sensing mechanism ensures a robust cytoprotective response. The Nrf2 regulatory network includes drug metabolizing, antioxidant, anti-inflammatory and metabolic enzymes, and affects mitochondrial function. Abnormal mitochondrial function is seen in patients with various neurological conditions, such as epilepsy, frontotemporal dementia, and Parkinson’s disease, and pharmacological Nrf2 activation with electrophilic inducers, some of which are in clinical trials, shows beneficial effects in cell culture and animal models of these conditions.

Electrophilic targeting of Keap1/Nrf2 signalling for disease prevention and treatment

256th National Meeting (2018)

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