Title: Discovery of (R)-2-(6-Methoxynaphthalen-2-yl)butanoic Acid as a Potent and Selective Aldo-keto Reductase 1C3 Inhibitor.
Authors: Adeniji, Adegoke; Uddin, Md Jashim; Zang, Tianzhu; Tamae, Daniel; Wangtrakuldee, Phumvadee; Marnett, Lawrence J; Penning, Trevor M
Published In J Med Chem, (2016 Aug 25)
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.
PubMed ID: 27486833
MeSH Terms: 3-Hydroxysteroid Dehydrogenases/antagonists & inhibitors*; 3-Hydroxysteroid Dehydrogenases/metabolism; Aldo-Keto Reductase Family 1 Member C3; Butyrates/chemical synthesis; Butyrates/chemistry; Butyrates/pharmacology*; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Discovery*; Enzyme Inhibitors/chemical synthesis; Enzyme Inhibitors/chemistry; Enzyme Inhibitors/pharmacology*; Humans; Hydroxyprostaglandin Dehydrogenases/antagonists & inhibitors*; Hydroxyprostaglandin Dehydrogenases/metabolism; Molecular Structure; Naphthalenes/chemical synthesis; Naphthalenes/chemistry; Naphthalenes/pharmacology*; Structure-Activity Relationship