Emerging substrate proteins of Kelch-like ECH associated protein 1 (Keap1) and potential challenges for the development of small-molecule inhibitors of the Keap1-nuclear factor erythroid 2-related factor 2 (Nrf2) protein-protein interaction.

The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is believed to combat both oxidative stress and inflammation as a promising strategy to treat chronic diseases. Recently, directly inhibiting the protein-protein interaction (PPI) between Nrf2 and Kelch-like ECH associated protein 1 (Keap1) has emerged as an attractive strategy to activate Nrf2 in organisms. The current development of Keap1-Nrf2 PPI inhibitors is mainly based on the interaction between Keap1 and the Nrf2 ETGE motif. However, a group of proteins that feature an ETGE motif similar to that of Nrf2 have emerged as new substrates of Keap1 over the last decade. In this Perspective, we focus on the potential off-target actions of current Keap1-Nrf2 PPI inhibitors and discuss their impact on future drug development. We also propose that a DLGex-based strategy aiming to inhibit the Keap1-Nrf2 DLGex interaction would help the development of small molecules with better target selectivity.