title: Improved therapeutic targeting of the androgen receptor: rational drug design improves survival in castration-resistant prostate cancer.
abstract: The growth and dependence of Prostate Cancer (PCa) on androgen stimulation led to the use of castration to reduce circulating levels of androgens and anti-androgens to directly target the androgen receptor (AR) ligand-binding domain (LBD). However, castration-resistant prostate cancer (CRPC) resistant to anti-androgens invariably develops and can be associated with AR genomic aberrations (mutations, amplification) and/or an increase in AR mRNA expression. Efforts to more effectively target the AR in CRPC led to the rational design of CYP17A1 inhibitors and more potent antiandrogens. The front-runner 2nd generation rationally-designed therapeutics targeting the AR, abiraterone and enzalutamide have been shown to improve survival and clinical outcome for CRPC patients. Several other CYP17A1 inhibitors and anti-androgens are in clinical and preclinical development. However, patients ultimately progress and current evidence suggests that this can occur through reactivation of AR signaling. Several ongoing programs aim to develop LBD independent therapeutic strategies that for example target the N terminus domain (NTD) of the AR or chaperone proteins. Rationally-designed approaches combining different strategies for targeting the AR or associated pathways also warrant clinical evaluation.
authors.affiliation: Section of Medicine, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, United Kingdom.
authors.forename: Ai Chiin
authors.initials: AC
authors.lastname: Lim
authors.forename: Gerhardt
authors.initials: G
authors.lastname: Attard
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use*; D000728:Androgens / Q000235:genetics / Q000378:metabolism; D000736:Androstenes; D000737:Androstenols / Q000627:therapeutic use; D001549:Benzamides; D002369:Castration / Q000379:methods; D002869:Chromosome Aberrations / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D008297:Male; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000627:therapeutic use; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000728:Androgens; D000736:Androstenes; D000737:Androstenols; D001549:Benzamides; D009570:Nitriles; D012333:RNA, Messenger; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; C089740:abiraterone