INTRODUCTION: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.
AREAS COVERED: AR antagonists whose patents published between 2008 and 2011 are reviewed. Antagonists are organized based on the screening paradigm reported as discussed above.
EXPERT OPINION: 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.
Written by:
Mohler ML, Coss CC, Duke CB 3rd, Patil SA, Miller DD, Dalton JT. Are you the author?
Preclinical Research and Development, GTx, Inc., 3 North Dunlap Street, Memphis, TN 38163, USA.
Reference: Expert Opin Ther Pat. 2012 May;22(5):541-65.
doi: 10.1517/13543776.2012.682571
PubMed Abstract
PMID: 22583332
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