Structure-based optimization and biological evaluation of human 20α-hydroxysteroid dehydrogenase (AKR1C1) salicylic acid-based inhibitors

详细信息    查看全文

• 作者：Ossama El-Kabbani ; Peter J. Scammells ; Tom Day ; Urmi Dhagat ; Satoshi Endo ; Toshiyuki Matsunaga ; Midori Soda ; Akira Hara
• 关键词：Aldo-keto reductase ; 3-Bromo-5-phenylsalicylic acid ; Cancer ; Drug design ; Human 20α ; -hydroxysteroid dehydrogenase ; Human 3α ; -hydroxysteroid dehydrogenase
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：November 2010
• 年：2010
• 卷：45
• 期：11
• 页码：5309-5317
• 全文大小：452 K

文摘

The tertiary structure of the Leu308Val mutant of human 20α-hydroxysteroid dehydrogenase (AKR1C1) in complex with the inhibitor 3,5-dichlorosalicylic acid (DCL) has been determined. Structures and kinetic properties of the wild-type and mutant enzymes indicate that Leu308 is a selectivity determinant for inhibitor binding. The Leu308Val mutation resulted in 13-fold and 3-fold reductions in the inhibitory potencies of DCL and 3-bromo-5-phenylsalicylic acid (BPSA), respectively. The replacement of Leu308 with an alanine resulted in 473-fold and 27-fold reductions in the potencies for DCL and BPSA, respectively. In our attempts to optimize inhibitor potency and selectivity we synthesized 5-substituted 3-chlorosalicylic acid derivatives, of which the most potent compound, 3-chloro-5-phenylsalicylic acid (K_i = 0.86 nM), was 24-fold more selective for AKR1C1 relative to the structurally similar 3α-hydroxysteroid dehydrogenase (AKR1C2). Furthermore, the compound inhibited the metabolism of progesterone in AKR1C1-overexpressed cells with an IC₅₀ value equal to 100 nM.