Zheng Jianwei, Wang Junfeng, Wang Qian, Zou Hongye, Wang Hong, Zhang Zhenhua, Chen Jianghe, Wang Qianqian, Wang Panxia, Zhao Yueshan, Lu Jing, Zhang Xiaolei, Xiang Songtao, Wang Haibin, Lei Jinping, Chen Hong-Wu, Liu Peiqing, Liu Yonghong, Han Fanghai, Wang Junjian
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
CAS Key Laboratory of Tropical Marine Bio-resources and Ecology/Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China.
Acta Pharm Sin B. 2020 Dec;10(12):2313-2322. doi: 10.1016/j.apsb.2020.07.001. Epub 2020 Jul 12.
Prostate cancer (PCa) patients who progress to metastatic castration-resistant PCa (mCRPC) mostly have poor outcomes due to the lack of effective therapies. Our recent study established the orphan nuclear receptor ROR as a novel therapeutic target for CRPC. Here, we reveal that elaiophylin (Elai), an antibiotic from , is a novel ROR antagonist and showed potent antitumor activity against CRPC and . We demonstrated that Elai selectively binded to ROR protein and potently blocked ROR transcriptional regulation activities. Structure-activity relationship studies showed that Elai occupied the binding pocket with several key interactions. Furthermore, Elai markedly reduced the recruitment of ROR to its genomic DNA response element (RORE), suppressed the expression of ROR target genes and variants, and significantly inhibited PCa cell growth. Importantly, Elai strongly suppressed tumor growth in both cell line based and patient-derived PCa xenograft models. Taken together, these results suggest that Elai is novel therapeutic ROR inhibitor that can be used as a drug candidate for the treatment of human CRPC.
进展为转移性去势抵抗性前列腺癌（mCRPC）的前列腺癌（PCa）患者由于缺乏有效的治疗方法，大多预后不良。我们最近的研究确定孤儿核受体ROR是CRPC的一个新的治疗靶点。在此，我们揭示了来自[具体来源未提及]的一种抗生素伊索霉素（Elai）是一种新型ROR拮抗剂，对CRPC和[具体细胞系未提及]显示出强大的抗肿瘤活性。我们证明Elai选择性地与ROR蛋白结合，并有力地阻断ROR转录调控活性。构效关系研究表明，Elai通过几个关键相互作用占据了结合口袋。此外，Elai显著减少ROR向其基因组DNA反应元件（RORE）的募集，抑制ROR靶基因[具体基因未提及]和[具体基因未提及]变体的表达，并显著抑制PCa细胞生长。重要的是，Elai在基于细胞系和患者来源的PCa异种移植模型中均强烈抑制肿瘤生长。综上所述，这些结果表明Elai是一种新型治疗性ROR抑制剂，可作为治疗人类CRPC的候选药物。
