Original articles
Jianwei Zheng, Junfeng Wang, Qian Wang, Hongye Zou, Hong Wang, Zhenhua Zhang, Jianghe Chen, Qianqian Wang, Panxia Wang, Yueshan Zhao, Jing Lu, Xiaolei Zhang, Songtao Xiang, Haibin Wang, Jinping Lei, Hong-Wu Chen, Peiqing Liu, Yonghong Liu, Fanghai Han, Junjian Wang. Targeting castration-resistant prostate cancer with a novel RORγ antagonist elaiophylin[J]. Acta Pharmaceutica Sinica B, 2020, 10(12): 2313-2322

Targeting castration-resistant prostate cancer with a novel RORγ antagonist elaiophylin
Jianwei Zhenga, Junfeng Wangb, Qian Wanga, Hongye Zouc, Hong Wanga, Zhenhua Zhanga, Jianghe Chena, Qianqian Wanga, Panxia Wanga, Yueshan Zhaoa, Jing Lua, Xiaolei Zhanga, Songtao Xiangd, Haibin Wange, Jinping Leia, Hong-Wu Chenc, Peiqing Liua,f,g, Yonghong Liub, Fanghai Hanh, Junjian Wanga,f,g
a School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China;
b 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;
c Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA;
d Department of Urology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, China;
e Department of Joint Orthopaedic, the First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510405, China;
f National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou 510006, China;
g Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China;
h Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
antibiotic from Actinomycete streptomyces, is a novel RORγ antagonist and showed potent antitumor activity against CRPC in vitro and in vivo. We demonstrated that Elai selectively binded to RORγ protein and potently blocked RORγ 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 RORγ to its genomic DNA response element (RORE), suppressed the expression of RORγ target genes AR and AR 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 RORγ inhibitor that can be used as a drug candidate for the treatment of human CRPC.
Key words:    RORγ    Castration-resistant prostate cancer    Nuclear receptor    Antagonist    Elaiophylin   
Received: 2020-03-13     Revised: 2020-06-20
DOI: 10.1016/j.apsb.2020.07.001
Funds: This research was supported by the National Natural Science Foundation of China (81872891, 81572925, 81774339 and 41776169), the Guangdong Natural Science Funds for Distinguished Young Scholar (No. 2019B151502016, China), the Science and Technology Planning Project of Guangdong Province (No. 2017A050506042, China), Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01Y093, China), National Major Special Projects for the Creation and Manufacture of New Drugs (2019ZX09301104, China), National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province, 2017B090903004, China), the Fundamental Research Funds for the Central Universities (No. 19ykzd23, China), Pearl River S&T Nova Program of Guangzhou (No. 201710010136, China).
Corresponding author: Yonghong Liu, yonghongliu@scsio.ac.cn;fh_han@163.com;Fanghai Han, Junjian Wang, wangjj87@mail.sysu.edu.cn     Email:yonghongliu@scsio.ac.cn;fh_han@163.com;wangjj87@mail.sysu.edu.cn
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Jianwei Zheng
Junfeng Wang
Qian Wang
Hongye Zou
Hong Wang
Zhenhua Zhang
Jianghe Chen
Qianqian Wang
Panxia Wang
Yueshan Zhao
Jing Lu
Xiaolei Zhang
Songtao Xiang
Haibin Wang
Jinping Lei
Hong-Wu Chen
Peiqing Liu
Yonghong Liu
Fanghai Han
Junjian Wang

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