Identification of novel functional inhibitors of 17β‐hydroxysteroid dehydrogenase type III (17β‐HSD3)

Background Endocrine therapy of prostate cancer (PCa) relies on agents which disrupt the biosynthesis of testosterone in the testis and/or by direct antagonism of active hormone on the androgen receptor (AR) in non-gonadal target tissues of hormone action such as the prostate. Methods In an effort to evaluate new therapies which could inhibit gonadal or non-gonadal testosterone biosynthesis, we developed high throughput biochemical and cellular screening assays to identify inhibitors of 17β-hydroxysteroid dehydrogenase type III (17β-HSD3), the enzyme catalyzing the conversion of androstenedione (AdT) to testosterone. Results Initial screening efforts identified a natural product, 18β-glycyrrhetinic acid, and a novel derivative of AdT, 3-O-benzylandrosterone, as potent inhibitors of the enzyme. Further efforts led to the identification of several classes of non-steroidal, low molecular weight compounds that potently inhibited 17β-HSD3 enzymatic activity. One of the most potent classes of 17β-HSD3 inhibitors was a series of anthranilamide small molecules identified from a collection of compounds related to non-steroidal modulators of nuclear hormone receptors. The anthranilamide based 17β-HSD3 inhibitors were exemplified by BMS-856, a compound displaying low nanomolar inhibition of 17β-HSD3 enzymatic activity. In addition, this series of compounds displayed potent inhibition of 17β-HSD3-mediated cellular conversion of AdT to testosterone and inhibited the 17β-HSD3-mediated conversion of testosterone necessary to promote AR-dependent transcription. Conclusions The identification of non-steroidal functional inhibitors of 17β-HSD3 may be a useful complementary approach for the disruption of testosterone biosynthesis in the treatment of PCa. © 2005 Wiley-Liss, Inc.