期刊
EXPERT OPINION ON THERAPEUTIC PATENTS
卷 22, 期 5, 页码 541-565出版社
INFORMA HEALTHCARE
DOI: 10.1517/13543776.2012.682571
关键词
androgen receptor antagonist; androgen receptor downregulating agent; androgen receptor pan-antagonist; bicalutamide; castration-resistant prostate cancer; MDV3100; noncompetitive androgen receptor antagonist; nuclear translocation inhibitor; selective androgen receptor degrader
资金
- GTx, Inc.
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. Apipeline 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.
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