title: Structure-Activity and Structure-Property Relationship and Exploratory in Vivo Evaluation of the Nanomolar Keap1-Nrf2 Protein-Protein Interaction Inhibitor.
abstract: Directly disrupting the Keap1-Nrf2 protein-protein interaction (PPI) is an effective way to activate Nrf2. Using the potent Keap1-Nrf2 PPI inhibitor that was reported by our group, we conducted a preliminary investigation of the structure-activity and structure-property relationships of the ring systems to improve the drug-like properties. Compound 18e, which bore p-acetamido substituents on the side chain phenyl rings, was the best choice for balancing PPI inhibition activity, physicochemical properties, and cellular Nrf2 activity. Cell-based experiments with 18e showed that the Keap1-Nrf2 PPI inhibitor can activate Nrf2 and induce the expression of Nrf2 downstream proteins in an Nrf2-dependent manner. An exploratory in vivo experiment was carried out to further evaluate the anti-inflammatory effects of 18e in a LPS-challenged mouse model. The primary results indicated that 18e could reduce the level of circulating pro-inflammatory cytokines induced by LPS and relieve the inflammatory response.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, China.|Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Zheng-Yu
authors.initials: ZY
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, China.|Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Li Li
authors.initials: LL
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, China.|Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Meng-Chen
authors.initials: MC
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, China.|Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Zhi-Yun
authors.initials: ZY
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, China.|Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Zhen-Wei
authors.initials: ZW
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, China.|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: Xiao-Li
authors.initials: XL
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, China.|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: Xiao-Ke
authors.initials: XK
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, China.|Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University , Nanjing 210009, China.|Department of Organic Chemistry, School of Science, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Xiao-Jin
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, China.|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: Hao-Peng
authors.initials: HP
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, China.|Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Qi-Dong
authors.initials: QD
authors.lastname: You
mesh_terms: D065767:Activation, Metabolic / Q000187:drug effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000494:pharmacology; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D000072019:Kelch-Like ECH-Associated Protein 1; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D034741:RNA, Small Interfering