Discovery of (R)-2-(6-Methoxynaphthalen-2-yl)butanoic Acid as a Potent and Selective Aldo-keto Reductase 1C3 Inhibitor.

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Adeniji A, Uddin MJ, Zang T, Tamae D, Wangtrakuldee P, Marnett LJ, Penning TM

Discovery of (R)-2-(6-Methoxynaphthalen-2-yl)butanoic Acid as a Potent and Selective Aldo-keto Reductase 1C3 Inhibitor.

J Med Chem. 2016 Aug 25;59(16):7431-44. doi: 10.1021/acs.jmedchem.6b00160. Epub 2016 Aug 12.

PubMed ID

27486833 [ View in PubMed

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Abstract

Type 5 17beta-hydroxysteroid dehydrogenase, aldo-keto reductase 1C3 (AKR1C3) converts Delta(4)-androstene-3,17-dione and 5alpha-androstane-3,17-dione to testosterone (T) and 5alpha-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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Androstenedione	Aldo-keto reductase family 1 member C3	Protein	Humans	Yes	Substrate Inducer	Details
Indomethacin	Aldo-keto reductase family 1 member C3	Protein	Humans	Unknown	Inhibitor	Details

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Androstanedione	Aldo-keto reductase family 1 member C3	Protein	Humans	Unknown	Substrate	Details
Androstenedione	Aldo-keto reductase family 1 member C3	Protein	Humans	No	Substrate	Details
Stanolone	Aldo-keto reductase family 1 member C3	Protein	Humans	Unknown	Product of	Details