Structural and mechanistic insights into the Keap1-Nrf2 system as a route to drug discovery |
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| Institution: | 1. Tumor Microenvironment Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea;2. Department of Pharmacy, College of Pharmacy, Keimyung University, Daegu, South Korea;3. Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea;4. C&C Research Laboratories, DRC, Sungyunkwan University, Suwon, South Korea;5. Department of Food Science and Biotechnology, College of Knowledge-based Services Engineering, Sungshin Women’s University, Seoul, South Korea;6. Cancer Research Institute, Seoul National University, Seoul, South Korea;1. Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, USA;2. Arizona Cancer Center, University of Arizona, Tucson, AZ, 85724, USA;1. IRBM Science Park S.p.A., Pomezia, Roma, Italy;2. CHDI Management/CHDI Foundation, Los Angeles, CA, USA;3. Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma “Tor Vergata”, Roma, Italy;1. Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA;2. Department of Pediatrics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA;3. Department of Biological Sciences Purdue University, West Lafayette, IN 47907, USA;4. Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA;5. University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA;1. Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, 833 S. Wood St., Chicago, IL 60612, United States;2. University of Illinois Cancer Center, University of Illinois at Chicago, 833 S. Wood St., Chicago, IL 60612, United States |
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| Abstract: | The proteins Keap1 and Nrf2 together act as a cytoprotective mechanism that enables cells to overcome electrophilic and oxidative stress. Research has shown that manipulating this system by modulating the Keap1-Nrf2 interaction either through inhibition at the binding interface or via the covalent modification of Keap1 could provide a powerful therapeutic strategy for a range of diseases. However, despite intensive investigation of the system and significant progress in the development of inhibitory small molecules, there is still much to learn about the pathways associated with the Keap1-Nrf2 system and the structural details underpinning its mechanism of action. In this review, we discuss how a deeper understanding could prove revolutionary in the development of new inhibitors and activators as well as guiding how to best harness Keap1 for targeted protein degradation. |
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