title: Discovery of (R)-2-(6-Methoxynaphthalen-2-yl)butanoic Acid as a Potent and Selective Aldo-keto Reductase 1C3 Inhibitor.
abstract: Type 5 17β-hydroxysteroid dehydrogenase, aldo-keto reductase 1C3 (AKR1C3) converts Δ(4)-androstene-3,17-dione and 5α-androstane-3,17-dione to testosterone (T) and 5α-dihydrotestosterone, respectively, in castration resistant prostate cancer (CRPC). In CRPC, AKR1C3 is implicated in drug resistance, and enzalutamide drug resistance can be surmounted by indomethacin a potent inhibitor of AKR1C3. We examined a series of naproxen analogues and find that (R)-2-(6-methoxynaphthalen-2-yl)butanoic acid (in which the methyl group of R-naproxen was replaced by an ethyl group) acts as a potent AKR1C3 inhibitor that displays selectivity for AKR1C3 over other AKR1C enzymes. This compound was devoid of inhibitory activity on COX isozymes and blocked AKR1C3 mediated production of T and induction of PSA in LNCaP-AKR1C3 cells as a model of a CRPC cell line. R-Profens are substrate selective COX-2 inhibitors and block the oxygenation of endocannabinoids and in the context of advanced prostate cancer R-profens could inhibit intratumoral androgen synthesis and act as analgesics for metastatic disease.
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics and the Center for Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania , 1315 BRBII/III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104-6160, United States.
authors.forename: Adegoke
authors.initials: A
authors.lastname: Adeniji
authors.affiliation: Departments of Biochemistry, Chemistry, and Pharmacology, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-0146, United States.
authors.forename: Md Jashim
authors.initials: MJ
authors.lastname: Uddin
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics and the Center for Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania , 1315 BRBII/III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104-6160, United States.
authors.forename: Tianzhu
authors.initials: T
authors.lastname: Zang
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics and the Center for Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania , 1315 BRBII/III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104-6160, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tamae
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics and the Center for Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania , 1315 BRBII/III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104-6160, United States.
authors.forename: Phumvadee
authors.initials: P
authors.lastname: Wangtrakuldee
authors.affiliation: Departments of Biochemistry, Chemistry, and Pharmacology, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-0146, United States.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics and the Center for Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania , 1315 BRBII/III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104-6160, United States.
authors.forename: Trevor M
authors.initials: TM
authors.lastname: Penning
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000074425:Aldo-Keto Reductase Family 1 Member C3; D002087:Butyrates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000619731:(R)-2-(6-methoxynaphthalen-2-yl)butanoic Acid; D002087:Butyrates; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3