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J Med Chem. 2012 Sep 13;55(17):7417-24. doi: 10.1021/jm300841n. Epub 2012 Aug 27.

Selective inhibitors of aldo-keto reductases AKR1C1 and AKR1C3 discovered by virtual screening of a fragment library.

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Institute of Biochemistry, Faculty of Medicine, University of Ljubljana , Vrazov trg 2, 1000 Ljubljana, Slovenia.


Human aldo-keto reductases 1C1-1C4 (AKR1C1-AKR1C4) 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-AKR1C4 enzymes. Twenty-four structurally diverse compounds were discovered with low μM 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 μM, exceeding expected activity for fragments. The compounds identified represent an excellent starting point for further hit-to-lead development.

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