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.
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.
State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University , Nanjing 210009, China.|Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, China.
Zheng-Yu
ZY
Jiang
State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University , Nanjing 210009, China.
Meng-Chen
MC
Lu
State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University , Nanjing 210009, China.|Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, China.
Qi-Dong
QD
You
D000818:Animals; D055808:Drug Discovery; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000037:antagonists & inhibitors*; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors*; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D054852:Small Molecule Libraries