Department of Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
Cancer Res. 2011 Feb 15;71(4):1208-13. doi: 10.1158/0008-5472.CAN_10-3398. Epub 2011 Feb 1.
Androgen ablation therapy remains the gold standard for the treatment of advanced prostate cancer, but unfortunately, it is not curative, and eventually the disease will return as lethal castration-resistant prostate cancer (CRPC). Mounting evidence supports the concept that development of CRPC is causally related to continued transactivation of androgen receptor (AR). All current therapies that target the AR are dependent on the presence of its C-terminal ligand-binding domain (LBD). However, it is the N-terminal domain (NTD) of the AR that is the "Achilles' heel" of AR activity, with AF-1 being essential for AR activity regardless of androgen. Recent efforts to develop drugs to the AR NTD have yielded EPI-001, a small molecule, sintokamide peptides, and decoys to the AR NTD with EPI-001, the best characterized and most promising for clinical development based upon specificity, low toxicity, and cytoreductive antitumor activity.
雄激素剥夺疗法仍然是治疗晚期前列腺癌的金标准，但不幸的是，它不能治愈疾病，最终疾病会以致命的去势抵抗性前列腺癌（CRPC）复发。越来越多的证据支持这样一种概念，即 CRPC 的发展与雄激素受体（AR）的持续转激活有因果关系。所有目前针对 AR 的治疗方法都依赖于其 C 端配体结合域（LBD）的存在。然而，AR 的 N 端结构域（NTD）才是 AR 活性的“阿喀琉斯之踵”，无论雄激素是否存在，AF-1 都是 AR 活性所必需的。最近开发针对 AR NTD 的药物的努力取得了 EPI-001、小分子 sintokamide 肽和 AR NTD 的诱饵等成果，EPI-001 是最具特异性、低毒性和细胞减少抗肿瘤活性的药物，最有希望用于临床开发。
