Discovery and Development of Keap1-Nrf2 Protein-Protein Interaction Inhibitors

The transcription factor Nrf2 is in charge of the cellular defense system, and enhancing Nrf2 activity has potential usages in various inflammatory diseases. Recently, directly inhibiting Keap1-Nrf2 protein-protein interactions as a novel Nrf2-modulating strategy has many advantages over using electrophilic Nrf2 activators. The development of Keap1-Nrf2 protein-protein interaction inhibitors has become a topic of intense research, and potent inhibitors of this target have been identified. This chapter summarizes the progress in the discovery and development of Keap1-Nrf2 PPI inhibitors, including the Keap1-Nrf2 regulatory system, screening assay for inhibitor identification, different methods in the development of inhibitors. We also summarized the chemotypes of inhibitors, stated the structure–activity relationship, as well as discussed privileged structures.