Structure-based design, synthesis and in vitro characterization of potent 17beta-hydroxysteroid dehydrogenase type 1 inhibitors based on 2-substitutions of estrone and D-homo-estrone.

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Moller G, Deluca D, Gege C, Rosinus A, Kowalik D, Peters O, Droescher P, Elger W, Adamski J, Hillisch A

Structure-based design, synthesis and in vitro characterization of potent 17beta-hydroxysteroid dehydrogenase type 1 inhibitors based on 2-substitutions of estrone and D-homo-estrone.

Bioorg Med Chem Lett. 2009 Dec 1;19(23):6740-4. doi: 10.1016/j.bmcl.2009.09.113. Epub 2009 Oct 3.

PubMed ID
19836949 [ View in PubMed
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Abstract

In search for specific drugs against steroid-dependent cancers we have developed a novel set of potent inhibitors of steroidogenic human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD 1). The X-ray structure of 17beta-HSD 1 in complex with estradiol served as basis for the design of the inhibitors. 2-Substituted estrone and D-homo-estrone derivatives were synthesized and tested for 17beta-HSD 1 inhibition. The best 17beta-HSD 1 inhibitor, 2-phenethyl-D-homo-estrone, revealed an IC(50) of 15 nM in vitro. The inhibitory potency of compounds is comparable or better to that of previously described inhibitors. An interaction within the cofactor binding site is not necessary to obtain this high binding affinity for substances developed.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
EstradiolEstrogen receptor alphaIC 50 (nM)12.5N/AN/ADetails
EstroneEstrogen receptor alphaIC 50 (nM)96N/AN/ADetails