Discovery and Development of Kelch-like ECH-Associated Protein 1. Nuclear Factor Erythroid 2‑Related Factor 2 (KEAP1:NRF2) Protein–Protein Interaction Inhibitors: Achievements, Challenges, and Future Directions

• Published in: Journal of medicinal chemistry Vol. 59; no. 24; pp. 10837 - 10858
• Main Authors: Jiang, Zheng-Yu, Lu, Meng-Chen, You, Qi-Dong
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 22.12.2016
• Subjects: Animals; Drug Discovery; Humans; Kelch-Like ECH-Associated Protein 1 - antagonists & inhibitors; NF-E2-Related Factor 2 - antagonists & inhibitors; Protein Binding - drug effects; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00586

The transcription factor Nrf2 is the primary regulator of the cellular defense system, and enhancing Nrf2 activity has potential usages in various diseases, especially chronic age-related and inflammatory diseases. Recently, directly targeting Keap1–Nrf2 protein–protein interaction (PPI) has been an emerging strategy to selectively and effectively activate Nrf2. This Perspective summarizes the progress in the discovery and development of Keap1–Nrf2 PPI inhibitors, including the Keap1–Nrf2 regulatory mechanisms, biochemical techniques for inhibitor identification, and approaches for identifying peptide and small-molecule inhibitors, as well as discusses privileged structures and future directions for further development of Keap1–Nrf2 PPI inhibitors.