title: Androgen receptor antagonists: a patent review (2008-2011).
abstract: BACKGROUND
  Androgen receptor (AR) antagonists are predominantly used as chemical castration to treat prostate cancer (i.e., in conjunction with androgen deprivation therapy (ADT)). Unfortunately, castration-resistant prostate cancer (CRPC) typically develops that is refractory to targeted therapy. Insights into CRPC biology have led to the emergence of a promising clinical candidate MDV3100 (1) and a resurgence in this field. A pipeline of preclinical competitive (C-terminally directed) antagonists was discovered using a variety of innovative screening paradigms. Some inhibit nuclear translocation, selectively downregulate or degrade AR (SARD), antagonize wild-type and escape mutant AR (pan-antagonists) and/or antagonize AR target organs in vivo. Separately, the N-terminal domain has emerged as a promising novel target for noncompetitive antagonists.
  
  
  METHODS
  AR antagonists whose patents published between 2008 and 2011 are reviewed. Antagonists are organized based on the screening paradigm reported as discussed above.
  
  
  CONCLUSIONS
  Novel mechanisms provide a more informed basis for selecting a competitive antagonist; however, high potency and favorable in vivo properties remain paramount. Noncompetitive antagonists have theoretical advantages suggestive of improved clinical efficacy, but no clinical proof of concept as of yet.
authors.affiliation: Preclinical Research and Development, GTx, Inc., 3 North Dunlap Street, Memphis, TN 38163, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Mohler
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Coss
authors.forename: Charles B
authors.initials: CB
authors.lastname: Duke
authors.forename: Shivaputra A
authors.initials: SA
authors.lastname: Patil
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
mesh_terms: D059002:Androgen Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007880:Legislation, Drug; D008297:Male; D015394:Molecular Structure; D009154:Mutation; D010330:Patents as Topic; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport; D011944:Receptors, Androgen / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D018931:Antineoplastic Agents, Hormonal; D011944:Receptors, Androgen