Identification of novel functional inhibitors of 17beta-hydroxysteroid dehydrogenase type III (17beta-HSD3)

• Published in: The Prostate 2005-10, Vol.65 (2), p.159-170
• Main Authors: Spires, Thomas E, Fink, Brian E, Kick, Ellen K, You, Dan, Rizzo, Cheryl A, Takenaka, Ivone, Lawrence, R Michael, Ruan, Zheming, Salvati, Mark E, Vite, Gregory D, Weinmann, Roberto, Attar, Ricardo M, Gottardis, Marco M, Lorenzi, Matthew V
• Format: Article
• Language: English
• Subjects: 17-Hydroxysteroid Dehydrogenases - antagonists & inhibitors; 17-Hydroxysteroid Dehydrogenases - physiology; Androstenedione - metabolism; Anti-Inflammatory Agents - pharmacology; Drug Evaluation, Preclinical; Glycyrrhetinic Acid - pharmacology; Humans; Male; ortho-Aminobenzoates - pharmacology; Prostatic Neoplasms - drug therapy; Testosterone - biosynthesis
• ISSN: 0270-4137

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. 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 17beta-hydroxysteroid dehydrogenase type III (17beta-HSD3), the enzyme catalyzing the conversion of androstenedione (AdT) to testosterone. Initial screening efforts identified a natural product, 18beta-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 17beta-HSD3 enzymatic activity. One of the most potent classes of 17beta-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 17beta-HSD3 inhibitors were exemplified by BMS-856, a compound displaying low nanomolar inhibition of 17beta-HSD3 enzymatic activity. In addition, this series of compounds displayed potent inhibition of 17beta-HSD3-mediated cellular conversion of AdT to testosterone and inhibited the 17beta-HSD3-mediated conversion of testosterone necessary to promote AR-dependent transcription. The identification of non-steroidal functional inhibitors of 17beta-HSD3 may be a useful complementary approach for the disruption of testosterone biosynthesis in the treatment of PCa.