作用于雄激素受体不同结合位点的前列腺癌治疗药物的研究进展

Research progress on prostate cancer drugs targeting different sites of androgen receptor

前列腺癌是最常见的男性泌尿生殖系统的恶性肿瘤。雄激素受体在前列腺癌的发生、发展中起着重要作用。目前,所有治疗前列腺癌的药物(包括第一代的氟他胺、比卡鲁胺、尼鲁米特和第二代的恩扎鲁胺)都与雄激素受体的配体结合口袋结合,并且这些药物有着相似的分子结构,这可能引起药物之间的交叉耐药。为了避免耐药性的产生,研究者们致力于发现雄激素受体上新的药物结合位点。除雄激素受体配体结合位点外,主要对作用于氮端结合位点上的第一活性功能区(AF1)、第二活性功能区(AF2)、AF2附近的第三结合功能区(BF3)和DNA结合位点(DBD)的药物进行综述。

Prostate cancer is the most common malignant tumor of male urogenital system. The androgen receptor plays an important role in the occurrence and progression of prostate cancer. So far, all prostate cancer drugs including the first generation antiandrogens flutamide, bicalutamide, nilutamide, and the second generation enzalutamide, are combined with androgen receptor ligand binding pocket. In addition, they share a similar molecular scaffold which increases the likelihood of cross resistance. Accordingly, alternative sites of the androgen receptor have been attempted to overcome resistance to these anti-androgens. Besides ligand binding domain, prostate cancer drugs targeting active function 1（AF1） in N-terminal domain, active function 2（AF2）, binding function 3（BF3） near AF2, and DNA binding domain（DBD） are reviewed.