Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua, 321004, PR China; Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China.
Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua, 321004, PR China.
Eur J Med Chem. 2019 Mar 15;166:232-242. doi: 10.1016/j.ejmech.2019.01.036. Epub 2019 Jan 26.
Prostate cancer (PCa) is the most frequently diagnosed male malignant tumor and remains the second leading cause of male cancer mortality in the western countries. The second-generation antiandrogen enzalutamide (ENZa) can prolong survival time for patients with mCRPC. However, the overexpression of glucocorticoids receptor (GR) in mCRPC cells causes the resistance of antiandrogen and leads to the failure of androgen receptor (AR) targeting therapy. Herein, based on the chemical structures of antiandrogen and crystal structure of GR, we set up to develop GR/AR (GR and AR) dual antagonist by virtual screening and biological evaluation. We identified Z19 as a dual AR/GR antagonist. Z19 inhibited the transcription activity of both AR and GR, reducing both protein and mRNA level of the downstream proteins of GR and AR signaling, and provided a potential lead compound for the development of novel treatment agents of prostate cancer. Our work demonstrates that rational drug design is an efficient strategy in development of the GR/AR dual antagonist for the treatment of prostate cancer.
前列腺癌（PCa）是男性最常见的恶性肿瘤，也是西方国家男性癌症死亡的第二大主要原因。第二代抗雄激素恩杂鲁胺（ENZa）可以延长 mCRPC 患者的生存时间。然而，mCRPC 细胞中糖皮质激素受体（GR）的过度表达导致抗雄激素的耐药性，从而导致雄激素受体（AR）靶向治疗失败。在此，基于抗雄激素的化学结构和 GR 的晶体结构，我们通过虚拟筛选和生物评价来开发 GR/AR（GR 和 AR）双重拮抗剂。我们鉴定出 Z19 是一种双重 AR/GR 拮抗剂。Z19 抑制 AR 和 GR 的转录活性，降低 GR 和 AR 信号下游蛋白的蛋白和 mRNA 水平，为开发治疗前列腺癌的新型治疗药物提供了潜在的先导化合物。我们的工作表明，合理的药物设计是开发用于治疗前列腺癌的 GR/AR 双重拮抗剂的有效策略。
