Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 66, Issue 14, Pages 9325-9344Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.3c00712
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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.
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.
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