The design of novel 17β-hydroxysteroid dehydrogenase type 3 inhibitors

Abstract 17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed at high levels in the testes and seminal vesicles but has also been shown to be present in prostate tissue, suggesting its potential involvement in both gonadal and non-gonadal testosterone biosynthesis. The role of 17β-HSD3 in testosterone biosynthesis makes this enzyme an attractive molecular target for small molecule inhibitors for the treatment of prostate cancer. Here we report the design of selective inhibitors of 17β-HSD3 as potential anti-cancer agents. Due to 17β-HSD3 being a membrane-bound protein a crystal structure is not yet available. A homology model of 17β-HSD3 has been built to aid structure-based drug design. This model has been used with docking studies to identify a series of lead compounds that may give an insight as to how inhibitors interact with the active site. Compound 1 was identified as a potent selective inhibitor of 17β-HSD3 with an IC 50  = 700 nM resulting in the discovery of a novel lead series for further optimisation. Using our homology model as a tool for inhibitor design compound 5 was discovered as a novel potent and selective inhibitor of 17β-HSD3 with an IC 50 ∼200 nM.