title: Rational design of novel antiandrogens for neutralizing androgen receptor function in hormone refractory prostate cancer.
abstract: BACKGROUND
  The standard hormonal therapy with currently available antiandrogens and the leutinizing hormone releasing hormone (LHRH) analogs is not effective in the hormone-refractory stage of prostate cancer due to changes in androgen receptor (AR) signaling axis. In this refractory stage, AR continues to play a significant role in the growth of cancer cells even though the cancer cells are no longer dependent on the level of circulating androgens.
  
  
  METHODS
  A series of 11beta-Delta(9)-19 nortestosterone compounds were designed through structure-based rationale and tested for their binding affinity against AR and glucocorticoid receptor (GR) using fluorescence polarization assays, their agonistic ability to induce AR dependent transcription using PSA-driven report gene assays, and their growth inhibitory affects against a series of AR positive (LAPC4, LNCap, and CWR22R) and negative human prostate cancer cell lines (PC3) using MTT cell proliferation assays.
  
  
  RESULTS
  This study proposes the design of novel bifunctional antiandrogens based on the conjugation of 11beta and/or 7alpha-Delta(9)-19 nortestosterone class of steroidal compounds to the synthetic ligand for FK506-binding proteins. As a critical step towards the development of bifunctional antiandrogens, highly potent and AR-specific lead compounds were identified using in vitro data. The lead compounds identified in this study possessed low binding affinity for GR, indicating the absence of undesirable antiglucocorticoid activity.
  
  
  CONCLUSIONS
  The results of this study validate our drug discovery rationale based on the structural biology of AR and pave the pay for future development of bifunctional compounds in order to block AR function in hormone refractory stage of prostate cancer.
authors.affiliation: Chemical and Biomolecular Engineering, Whiting School of Engineering, Baltimore, Maryland, USA.
authors.forename: Pratap
authors.initials: P
authors.lastname: Singh
authors.forename: Gurulingappa
authors.initials: G
authors.lastname: Hallur
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Anchoori
authors.forename: Oladapo
authors.initials: O
authors.lastname: Bakare
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kageyama
authors.forename: Saeed R
authors.initials: SR
authors.lastname: Khan
authors.forename: John T
authors.initials: JT
authors.lastname: Isaacs
mesh_terms: D000726:Androgen Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D059002:Androgen Receptor Antagonists; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D015195:Drug Design; D005454:Fluorescence Polarization; D005562:Formazans / Q000737:chemistry; D006801:Humans; D008297:Male; D009277:Nandrolone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D013778:Tetrazolium Salts / Q000737:chemistry; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D005562:Formazans; D011944:Receptors, Androgen; D013778:Tetrazolium Salts; C079782:MTT formazan; D009277:Nandrolone; D017430:Prostate-Specific Antigen