Medicinal Chemistry Insights into the Development of Small-Molecule Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1-Nrf2) Protein-Protein Interaction Inhibitors

Oxidative stress has been implicatedin a wide rangeof pathologicalconditions. The transcription factor nuclear factor erythroid 2-relatedfactor 2 (Nrf2) exerts a central role in regulating the cellular defensesystem against oxidative and electrophilic insults. Nonelectrophilicinhibition of the protein-protein interaction (PPI) betweenKelch-like ECH-associated protein 1 (Keap1) and Nrf2 has become apromising approach to activate Nrf2. Recently, multiple drug discoverystrategies have facilitated the development of small-molecule Keap1-Nrf2PPI inhibitors with potent activity and favorable drug-like properties.In this Perspective, we summarize the latest progress of small-moleculeKeap1-Nrf2 PPI inhibitors from medicinal chemistry insightsand discuss future prospects and challenges in this field.

Automated summary

Oxidative stress is associated with various pathological conditions, and the transcription factor Nrf2 plays a crucial role in regulating cellular defense against oxidative and electrophilic damage. Inhibiting the protein-protein interaction (PPI) between Keap1 and Nrf2 through non-electrophilic means has emerged as a promising approach to activate Nrf2. Recent advances in drug discovery have led to the development of small-molecule Keap1-Nrf2 PPI inhibitors with potent activity and favorable drug-like properties. This Perspective summarizes the latest progress in this field and discusses future prospects and challenges.