The transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) is one of the primary regulators of the adaptive stress response, because it regulates expression of phase II metabolic enzymes, such as glutathione S-transferases (GST), NADPH:quinone oxidoreductase 1 (NQO1), and UDP glucuronosyl transferases (UGTs). Disrupting the association of Nrf2 with its negative regulator Kelch-like ECH-associated protein-1 (Keap1) may aid in prevention or therapy of disease states made worse by electrophilic or oxidative stresses. Electrophilic small molecules are known to react with Keap1 Cys residues, which in turn leads to disruption of the Keap1/Nrf2 complex and activation of Nrf2; although some of these are clinically used therapeutics, many of these electrophiles are known to interact with other biological targets. It has been hypothesized that non-electrophilic activators of Nrf2 might be more selective and could be developed by directly inhibiting the Keap1/Nrf2 interaction. We have developed structure-activity relationships (SARs) of non-electrophilic Keap1/Nrf2 inhibitors to ascertain what functional groups are important for binding to Keap1 and, thus, activation of Nrf2. We have carried out both biochemical interaction assays, as well as cell-based assays of Nrf2 function. Using these SARs, we have enhanced the potency and physicochemical properties of known Keap1-Nrf2 inhibitors.

Development of inhibitors of the Keap1/Nrf2 interactions

248th National Meeting (2014)

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