Section of Medicine, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, United Kingdom.
Curr Drug Targets. 2013 Apr;14(4):408-19. doi: 10.2174/1389450111314040003.
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.
前列腺癌（PCa）的生长和对雄激素刺激的依赖导致使用去势来降低循环中的雄激素和抗雄激素水平，从而直接靶向雄激素受体（AR）配体结合域（LBD）。然而，抗雄激素治疗抵抗的去势抵抗性前列腺癌（CRPC）不可避免地会发展，并可能与 AR 基因组异常（突变、扩增）和/或 AR mRNA 表达增加有关。为了更有效地靶向 CRPC 中的 AR，人们设计了 CYP17A1 抑制剂和更有效的抗雄激素药物。作为针对 AR 的第二代合理设计的治疗药物的领跑者，阿比特龙和恩杂鲁胺已被证明可以改善 CRPC 患者的生存和临床结局。还有几种其他的 CYP17A1 抑制剂和抗雄激素药物正在临床和临床前开发中。然而，患者最终会进展，目前的证据表明，这可能是通过 AR 信号的重新激活。目前正在开展几个项目，旨在开发独立于 LBD 的治疗策略，例如靶向 AR 的 N 端结构域（NTD）或伴侣蛋白。针对 AR 或相关途径的不同策略的合理设计方法也值得临床评估。
