Direct small-molecule inhibitors of the Keap1-Nrf2 protein-protein interaction: Scaffold evolution, PROTAC strategies, and therapeutic implications

The Keap1-Nrf2 signaling pathway is recognized as a central regulator of cellular protection against oxidative and electrophilic stress, and its pharmacological modulation has attracted considerable attention in drug discovery. Disruption of the Keap1-Nrf2 protein-protein interaction (PPI) has been proposed as an effective strategy to stabilize and activate Nrf2, thereby enhancing the expression of cytoprotective genes. In this review, we provide a comprehensive overview of recent progress in developing direct small-molecule Keap1-Nrf2 PPI inhibitors, spanning diverse chemotypes such as tetrahydroisoquinoline, 1,4-diaminonaphthalene, and other privileged scaffolds. We further summarize advances in Keap1-based PROTACs, one class of which employs targeted Keap1 degradation as an alternative strategy to achieve sustained Nrf2 activation. Special emphasis is placed on the evolution of structure-activity relationships (SAR), optimization of drug-like properties, and validation of pharmacological efficacy in preclinical models, covering disorders such as acute renal and hepatic injury, chronic lung disorders, neurodegeneration, and metabolic dysfunction. Together, these findings underscore the translational potential of Nrf2 activators in various disease contexts and highlight Keap1 as an attractive therapeutic target for future medicinal chemistry efforts.