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 LBDindependent
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
Keywords: Abiraterone, castration-resistant prostate cancer, enzalutamide, androgen receptor
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