4FAL

Crystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 in complex with 3-((3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)-N-methylbenzamide (80)

4FAL の概要

• エントリーDOI: 10.2210/pdb4fal/pdb
• 関連するPDBエントリー: 4FA3 4FAM
• 分子名称: Aldo-keto reductase family 1 member C3, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 3-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)-N-methylbenzamide, ... (5 entities in total)
• 機能のキーワード: aldo-keto reductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P42330
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 39237.38

構造登録者

Turnbull, A.P.,Jamieson, S.M.F.,Brooke, D.G.,Heinrich, D.,Atwell, G.J.,Silva, S.,Hamilton, E.J.,Rigoreau, L.J.M.,Trivier, E.,Soudy, C.,Samlal, S.S.,Owen, P.J.,Schroeder, E.,Raynham, T.,Flanagan, J.U.,Denny, W.A. (登録日: 2012-05-22, 公開日: 2012-10-10, 最終更新日: 2023-09-13)

主引用文献

Jamieson, S.M.,Brooke, D.G.,Heinrich, D.,Atwell, G.J.,Silva, S.,Hamilton, E.J.,Turnbull, A.P.,Rigoreau, L.J.,Trivier, E.,Soudy, C.,Samlal, S.S.,Owen, P.J.,Schroeder, E.,Raynham, T.,Flanagan, J.U.,Denny, W.A.
3-(3,4-Dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic acids; a New Class of Highly Potent and Selective Inhibitors of the Type 5 17-beta-hydroxysteroid Dehydrogenase AKR1C3
J.Med.Chem., 55:7746-7758, 2012

PubMed 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 to bind in an adjacent hydrophobic pocket. SAR studies around this lead showed that the positioning of the carboxylate was critical, although it could be substituted by acid isosteres and amides. Small substituents on the dihydroisoquinoline gave improvements in potency. A set of "reverse sulfonamides" showed a 12-fold preference for the R stereoisomer. The compounds showed good cellular potency, as measured by inhibition of AKR1C3 metabolism of a known dinitrobenzamide substrate, with a broad rank order between enzymic and cellular activity, but amide analogues were more effective than predicted by the cellular assay.

PubMed: 22877157
DOI: 10.1021/jm3007867

実験手法

X-RAY DIFFRACTION (2 Å)