3-(3, 4-Dihydroisoquinolin-2 (1 H)-ylsulfonyl) benzoic Acids: Highly Potent and Selective Inhibitors of the Type 5 17-β-Hydroxysteroid Dehydrogenase AKR1C3

…, DG Brooke, D Heinrich, GJ Atwell, S Silva…

Index: Jamieson, Stephen M. F.; Brooke, Darby G.; Heinrich, Daniel; Atwell, Graham J.; Silva, Shevan; Hamilton, Emma J.; Turnbull, Andrew P.; Rigoreau, Laurent J. M.; Trivier, Elisabeth; Soudy, Christelle; Samlal, Sharon S.; Owen, Paul J.; Schroeder, Ewald; Raynham, Tony; Flanagan, Jack U.; Denny, William A. Journal of Medicinal Chemistry, 2012 , vol. 55, # 17 p. 7746 - 7758

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Citation Number: 20

Abstract

A high-throughput screen identified 3-(3, 4-dihydroisoquinolin-2 (1H)-ylsulfonyl) benzoic acid as a novel, highly potent (low nM), and isoform-selective (1500-fold) inhibitor of aldo- keto reductase AKR1C3: a target of interest in both breast and prostate cancer. Crystal structure studies showed that the carboxylate group occupies the oxyanion hole in the enzyme, while the sulfonamide provides the correct twist to allow the dihydroisoquinoline ...