title: Probing the structural requirements of non-electrophilic naphthalene-based Nrf2 activators.
abstract: Activation of the transcription factor Nrf2 has been posited to be a promising therapeutic strategy in a number of inflammatory and oxidative stress diseases due to its regulation of detoxifying enzymes. In this work, we have developed a comprehensive structure-activity relationship around a known, naphthalene-based non-electrophilic activator of Nrf2, and we report highly potent non-electrophilic activators of Nrf2. Computational docking analysis of a subset of the compound series demonstrates the importance of water molecule displacement for affinity, and the X-ray structure of di-amide 12e supports the computational analysis. One of the best compounds, acid 16b, has an IC50 of 61 nM in a fluorescence anisotropy assay and a Kd of 120 nM in a surface plasmon resonance assay. Additionally, we demonstrate that the ethyl ester of 16b is an efficacious inducer of Nrf2 target genes, exhibiting ex vivo efficacy similar to the well-known electrophilic activator, sulforaphane.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Atul D
authors.initials: AD
authors.lastname: Jain
authors.affiliation: Department of Pediatrics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Haranatha
authors.initials: H
authors.lastname: Potteti
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Richardson
authors.affiliation: Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Kingsley
authors.affiliation: Department of Biological Sciences Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Julia P
authors.initials: JP
authors.lastname: Luciano
authors.affiliation: Department of Biological Sciences Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Aya F
authors.initials: AF
authors.lastname: Ryuzoji
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Hyun
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Aleksej
authors.initials: A
authors.lastname: Krunic
authors.affiliation: Department of Biological Sciences Purdue University, West Lafayette, IN 47907, USA; Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Mesecar
authors.affiliation: Department of Pediatrics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA; University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Sekhar P
authors.initials: SP
authors.lastname: Reddy
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA; University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA. Electronic address: twmoore@uic.edu.
authors.forename: Terry W
authors.initials: TW
authors.lastname: Moore
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D051267:NF-E2-Related Factor 2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D009281:Naphthalenes; C031721:naphthalene
keywords: Cul3; Keap1; Keap1/Nrf2 interaction; Nrf2; Protein–protein interaction; Transcription factor