title: An inhibitor of the Keap1-Nrf2 protein-protein interaction protects NCM460 colonic cells and alleviates experimental colitis.
abstract: Ulcerative colitis (UC) is a chronic relapsing-remitting form of inflammatory bowel disease (IBD) that increases the risk of colorectal cancer, the third most common malignancy in humans. Oxidative stress is a risk factor for the development of UC. The Keap1-Nrf2-ARE pathway is one of the most important defensive mechanisms against oxidative and/or electrophilic stresses. In this study, we identified CPUY192018 as a potent small-molecule inhibitor of the Keap1-Nrf2 PPI, investigated the cyto-protective effects of CPUY192018 on the NCM460 colonic cells and evaluated whether treatment with the inhibitor of the Keap1-Nrf2 PPI exerts protection on an established experimental model of UC induced by dextran sodium sulfate (DSS). Our study clearly demonstrated that CPUY192018 had a cytoprotective effect against DSS in both NCM460 cells and mouse colon via the activation of Nrf2 signaling. These results suggested that activation of Nrf2 by directly inhibiting the Keap1-Nrf2 PPI may be beneficial as a treatment for UC.
authors.affiliation: 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, Nanjing 210009, China.
authors.forename: Meng-Chen
authors.initials: MC
authors.lastname: Lu
authors.affiliation: 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, Nanjing 210009, China.
authors.forename: Jian-Ai
authors.initials: JA
authors.lastname: Ji
authors.affiliation: 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, Nanjing 210009, China.
authors.forename: Yong-Lin
authors.initials: YL
authors.lastname: Jiang
authors.affiliation: 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, Nanjing 210009, China.
authors.forename: Zhi-Yun
authors.initials: ZY
authors.lastname: Chen
authors.affiliation: 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, Nanjing 210009, China.
authors.forename: Zhen-Wei
authors.initials: ZW
authors.lastname: Yuan
authors.affiliation: 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, Nanjing 210009, China.
authors.forename: Qi-Dong
authors.initials: QD
authors.lastname: You
authors.affiliation: 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, Nanjing 210009, China.
authors.forename: Zheng-Yu
authors.initials: ZY
authors.lastname: Jiang
mesh_terms: D000818:Animals; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D003106:Colon / Q000166:cytology* / Q000187:drug effects; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D056945:Hep G2 Cells; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D054852:Small Molecule Libraries; D016264:Dextran Sulfate