Phenyl Bis-Sulfonamide Keap1-Nrf2 Protein–Protein Interaction Inhibitors with an Alternative Binding Mode

Inhibitors of Kelch-like
ECH-associated protein 1 (Keap1) increase
the activity of the transcription factor nuclear factor erythroid
2-related factor 2 (Nrf2) by stalling its ubiquitination and degradation.
This enhances the expression of genes encoding proteins involved in
drug detoxification, redox homeostasis, and mitochondrial function.
Nrf2 activation offers a potential therapeutic approach for conditions
including Alzheimer’s and Parkinson’s diseases, vascular
inflammation, and chronic obstructive airway disease. Non-electrophilic
Keap1-Nrf2 protein–protein interaction (PPI) inhibitors may
have improved toxicity profiles and different pharmacological properties
to cysteine-reactive electrophilic inhibitors. Here, we describe and
characterize a series of phenyl bis-sulfonamide PPI inhibitors that
bind to Keap1 at submicromolar concentrations. Structural studies
reveal that the compounds bind to Keap1 in a distinct “peptidomimetic”
conformation that resembles the Keap1-Nrf2 ETGE peptide complex. This
is different to other small molecule Keap1-Nrf2 PPI inhibitors, including
bicyclic aryl bis-sulfonamides, offering a starting point for new
design approaches to Keap1 inhibitors.