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 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 clinical evaluation.
Keywords: Abiraterone, castration-resistant prostate cancer, enzalutamide, androgen receptor
Current Drug Targets
Title:Improved Therapeutic Targeting of the Androgen Receptor: Rational Drug Design Improves Survival in Castration-Resistant Prostate Cancer
Volume: 14 Issue: 4
Author(s): Ai Chiin Lim and Gerhardt Attard
Affiliation:
Keywords: Abiraterone, castration-resistant prostate cancer, enzalutamide, androgen receptor
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 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 clinical evaluation.
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Chiin Lim Ai and Attard Gerhardt, Improved Therapeutic Targeting of the Androgen Receptor: Rational Drug Design Improves Survival in Castration-Resistant Prostate Cancer, Current Drug Targets 2013; 14 (4) . https://dx.doi.org/10.2174/1389450111314040003
DOI https://dx.doi.org/10.2174/1389450111314040003 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
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