Selective Inhibitors of Aldo-Keto Reductases AKR1C1 and AKR1C3 Discovered by Virtual Screening of a Fragment Library

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• 作者：Petra Bro啪i膷 ; Samo Turk ; Adegoke O. Adeniji ; Janez Konc ; Du拧anka Jane啪i膷 ; Trevor M. Penning ; Tea Lani拧nik Ri啪ner ; Stanislav Gobec
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September 13, 2012
• 年：2012
• 卷：55
• 期：17
• 页码：7417-7424
• 全文大小：430K
• 年卷期：v.55,no.17(September 13, 2012)
• ISSN：1520-4804

文摘

Human aldo-keto reductases 1C1鈥?C4 (AKR1C1鈥揂KR1C4) function in vivo as 3-keto-, 17-keto-, and 20-ketosteroid reductases and regulate the activity of androgens, estrogens, and progesterone and the occupancy and transactivation of their corresponding receptors. Aberrant expression and action of AKR1C enzymes can lead to different pathophysiological conditions. AKR1C enzymes thus represent important targets for development of new drugs. We performed a virtual high-throughput screen of a fragment library that was followed by biochemical evaluation on AKR1C1鈥揂KR1C4 enzymes. Twenty-four structurally diverse compounds were discovered with low 渭M K_i values for AKR1C1, AKR1C3, or both. Two structural series included the salicylates and the N-phenylanthranilic acids, and additionally a series of inhibitors with completely novel scaffolds was discovered. Two of the best selective AKR1C3 inhibitors had K_i values of 0.1 and 2.7 渭M, exceeding expected activity for fragments. The compounds identified represent an excellent starting point for further hit-to-lead development.