title: Identification of novel functional inhibitors of 17beta-hydroxysteroid dehydrogenase type III (17beta-HSD3).
abstract: 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 17beta-hydroxysteroid dehydrogenase type III (17beta-HSD3), the enzyme catalyzing the conversion of androstenedione (AdT) to testosterone.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Oncology Drug Discovery, Bristol-Myers Squibb, Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Spires
authors.forename: Brian E
authors.initials: BE
authors.lastname: Fink
authors.forename: Ellen K
authors.initials: EK
authors.lastname: Kick
authors.forename: Dan
authors.initials: D
authors.lastname: You
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Rizzo
authors.forename: Ivone
authors.initials: I
authors.lastname: Takenaka
authors.forename: R Michael
authors.initials: RM
authors.lastname: Lawrence
authors.forename: Zheming
authors.initials: Z
authors.lastname: Ruan
authors.forename: Mark E
authors.initials: ME
authors.lastname: Salvati
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Vite
authors.forename: Roberto
authors.initials: R
authors.lastname: Weinmann
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Attar
authors.forename: Marco M
authors.initials: MM
authors.lastname: Gottardis
authors.forename: Matthew V
authors.initials: MV
authors.lastname: Lorenzi
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D000735:Androstenedione / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D006034:Glycyrrhetinic Acid / Q000494:pharmacology*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy; D013739:Testosterone / Q000096:biosynthesis*; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D062367:ortho-Aminobenzoates; D013739:Testosterone; D000735:Androstenedione; D015067:17-Hydroxysteroid Dehydrogenases; C476565:17beta-hydroxysteroid dehydrogenase type 3; D006034:Glycyrrhetinic Acid