Abstract
Aldo-keto reductase 1C3 (AKR1C3; type 5 17β-hydroxysteroid dehydrogenase) is overexpressed in castration resistant prostate cancer (CRPC) and is implicated in the intratumoral biosynthesis of testosterone and 5α-dihydrotestosterone. Selective AKR1C3 inhibitors are required because compounds should not inhibit the highly related AKR1C1 and AKR1C2 isoforms which are involved in the inactivation of 5α-dihydrotestosterone. NSAIDs, N-phenylanthranilates in particular, are potent but nonselective AKR1C3 inhibitors. Using flufenamic acid, 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid, as lead compound, five classes of structural analogues were synthesized and evaluated for AKR1C3 inhibitory potency and selectivity. Structure-activity relationship (SAR) studies revealed that a meta-carboxylic acid group relative to the amine conferred pronounced AKR1C3 selectivity without loss of potency, while electron withdrawing groups on the phenylamino B-ring were optimal for AKR1C3 inhibition. Lead compounds did not inhibit COX-1 or COX-2 but blocked the AKR1C3 mediated production of testosterone in LNCaP-AKR1C3 cells. These compounds offer promising leads toward new therapeutics for CRPC.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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20-Hydroxysteroid Dehydrogenases / antagonists & inhibitors
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3-Hydroxysteroid Dehydrogenases / antagonists & inhibitors*
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3-Hydroxysteroid Dehydrogenases / genetics
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3-Hydroxysteroid Dehydrogenases / metabolism
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Aldo-Keto Reductase Family 1 Member C3
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Cyclooxygenase 1 / metabolism
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Cyclooxygenase 2 / metabolism
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Cyclooxygenase Inhibitors / chemical synthesis
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Cyclooxygenase Inhibitors / chemistry
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Cyclooxygenase Inhibitors / pharmacology
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Fenamates / chemical synthesis*
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Fenamates / chemistry
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Fenamates / pharmacology
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Humans
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Hydroxyprostaglandin Dehydrogenases / antagonists & inhibitors*
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Hydroxyprostaglandin Dehydrogenases / genetics
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Hydroxyprostaglandin Dehydrogenases / metabolism
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Hydroxysteroid Dehydrogenases / antagonists & inhibitors
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Isoenzymes / antagonists & inhibitors
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Male
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Prostatic Neoplasms / drug therapy
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Structure-Activity Relationship
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Testosterone / antagonists & inhibitors
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Testosterone / biosynthesis
Substances
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Antineoplastic Agents
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Cyclooxygenase Inhibitors
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Fenamates
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Isoenzymes
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Testosterone
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3-Hydroxysteroid Dehydrogenases
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Hydroxysteroid Dehydrogenases
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20-Hydroxysteroid Dehydrogenases
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3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase
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Hydroxyprostaglandin Dehydrogenases
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AKR1C2 protein, human
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AKR1C3 protein, human
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Aldo-Keto Reductase Family 1 Member C3
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Cyclooxygenase 1
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Cyclooxygenase 2