First Structure–Activity Relationship of 17β-Hydroxysteroid Dehydrogenase Type 14 Nonsteroidal Inhibitors and Crystal Structures in Complex with the Enzyme

17β-HSD14 belongs
to the SDR family and oxidizes the hydroxyl
group at position 17 of estradiol and 5-androstenediol using NAD+ as cofactor. The goal of this study was to identify and optimize
17β-HSD14 nonsteroidal inhibitors as well as to disclose their
structure–activity relationship. In a first screen, a library
of 17β-HSD1 and 17β-HSD2 inhibitors, selected with respect
to scaffold diversity, was tested for 17β-HSD14 inhibition.
The most interesting hit was taken as starting point for chemical
modification applying a ligand-based approach. The designed compounds
were synthesized and tested for 17β-HSD14 inhibitory activity.
The two best inhibitors identified in this study have a very high
affinity to the enzyme with a Ki equal
to 7 nM. The strong affinity of these inhibitors to the enzyme active
site could be explained by crystallographic structure analysis, which
highlighted the role of an extended H-bonding network in the stabilization
process. The selectivity of the most potent compounds with respect
to 17β-HSD1 and 17β-HSD2 is also addressed.