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

In search for specific drugs against steroid-dependent cancers we have developed a novel set of potent inhibitors of steroidogenic human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD 1). The X-ray structure of 17β-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 17β-HSD 1 inhibition. The best 17β-HSD 1 inhibitor, 2-phenethyl-D-homo-estrone, revealed an IC50 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.

Graphical abstractThe development of 17β-HSD1 inhibitor (e.g., 2-phenethyl-D-homo-estrone with IC50 of 15 nM in vitro) is reported.Figure optionsDownload full-size imageDownload as PowerPoint slide