Oxidative stress is well recognized to contribute to the cause of a wide range of diseases, such as cancer, diabetes, Alzheimer's disease, arteriosclerosis, and inflammation. The Keap1–Nrf2–ARE pathway plays a critical regulatory role and can protect cells from oxidative stress through activating Nrf2 to induce its downstream phase II enzymes. Nrf2 activation through the covalent inactivation of Keap1 may cause unpredictable side effects. Non-covalent disruption of the Keap1–Nrf2 protein–protein interactions is an alternative strategy for Nrf2 activation, potentially with reduced risk of toxicity. Efforts have been made in recent years to develop peptide- and small molecule-based Keap1–Nrf2 PPI inhibitors via different approaches, including high-throughput screening, target-based virtual screening, structure-based optimization, and fragment-based drug design. This review aims to highlight the recently discovered small-molecule inhibitors as well as their therapeutic potential.

The Keap1-Nrf2-ARE pathway is one of the most important regulators of cytoprotective responses to oxidative and/or electrophilic stresses, which is believed to play a critical role in the development of many diseases, such as cancer, Alzheimer’s, Parkinson’s, and inflammatory bowel disease. Recent research indicates that the modulation of ARE activation via direct inhibition of the Keap1-Nrf2protein-protein interaction has many advantages, particularly the low cytotoxicity, over indirect covalent modulators of Keap1 protein for the discovery of novel small molecule modulators of this pathway. However, most known inducers (e.g., triterpenoids, isothiocyanates and sulfoxythiocarbamates) that activate the ARE system through electrophilic attacks on the cysteine sulfhydryl group of Keap1 also disrupt theKeap1-Nrf2 interaction. The understanding of co-crystal complex of the Keap1-Nrf2 interactionthus provides a structural basis for the rational design of highly potent direct inhibitors. This review summarizes the recent advances in the medicinal chemistry of small-molecule inhibitors in the areas of drug design, structure-activity relationships, and biological and biochemical properties. The peptides designed from DLG and ETGE motifs of Nrf2 protein that binds to Keap1 Kelch domain with promising binding affinities are highlighted. This review also includes recently reported non-peptide inhibitors with moderate inhibition by high-throughput screening. It is clear that further research is required for the discovery of more potent inhibitors.