title: Development of an aryl hydrocarbon receptor antagonist using the proteolysis-targeting chimeric molecules approach: a potential tool for chemoprevention.
abstract: Activation of the aryl hydrocarbon receptor (AHR) by agonists and environmental contaminants like dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) leads to many adverse biological effects, including tumor promotion. With this in mind, we propose that agents that block the AHR pathway may be therapeutically beneficial, particularly by exhibiting chemopreventive activities. In our current research, we have focused on the development of an AHR antagonist using a chemical genetic approach called PROTACS (PROteolysis-TArgeting Chimeric moleculeS). PROTACS is a novel approach of tagging small recognition sequences of a specific E3 ubiquitin ligase complex to a known ligand for the receptor of interest (AHR) for targeting its degradation. Here, we present the design and initial characterization of AHR targeting PROTACS (Apigenin-Protac) designed to degrade and inhibit the AHR in epithelial cells. Our results demonstrate the "proof of concept" of this approach in effectively blocking AHR activity in cultured cells.
authors.affiliation: Department of Molecular and Biomedical Pharmacology, MS305, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY40536, USA.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Puppala
authors.forename: Hyosung
authors.initials: H
authors.lastname: Lee
authors.forename: Kyung Bo
authors.initials: KB
authors.lastname: Kim
authors.forename: Hollie I
authors.initials: HI
authors.lastname: Swanson
mesh_terms: D047310:Apigenin / Q000737:chemistry / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018890:Chemoprevention / Q000379:methods*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000037:antagonists & inhibitors*; D013997:Time Factors
chemical_list: D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D047310:Apigenin; D004247:DNA; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D046988:Proteasome Endopeptidase Complex