Targeting castration-resistant prostate cancer with a novel RORγ antagonist elaiophylin

作     者：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 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

作者机构：School of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China CAS Key Laboratory of Tropical Marine Bio-resources and Ecology/Guangdong Key Laboratory of Marine Materia MedicaSouth China Sea Institute of OceanologyChinese Academy of SciencesGuangzhou 510301China Department of Biochemistry and Molecular MedicineUC Davis Comprehensive Cancer CenterSchool of MedicineUniversity of CaliforniaDavisSacramentoCA 95817USA Department of Urologythe Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhou 510120China Department of Joint Orthopaedicthe First Affiliated HospitalGuangzhou University of Chinese MedicineGuangzhou 510405China National-Local Joint Engineering Laboratory of Druggability and New Drugs EvaluationSun Yat-sen UniversityGuangzhou 510006China Guangdong Provincial Key Laboratory of New Drug Design and EvaluationSchool of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China Department of Gastrointestinal SurgerySun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2020年第10卷第12期

页      面：2313-2322页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1004[医学-公共卫生与预防医学(可授医学、理学学位)] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100214[医学-肿瘤学] 10[医学] 

基　　金：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) 

主　　题：RORγ Castration-resistant prostate cancer Nuclear receptor Antagonist Elaiophylin 

摘      要：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 RORγas a novel therapeutic target for CRPC.Here,we reveal that elaiophylin(Elai),an antibiotic from Actinomycete streptomyces,is a novel RORy antagonist and showed potent antitumor activity against CRPC in vitro and in vivo.We demonstrated that Elai selectively binded to RORy protein and potently blocked RORγtranscriptional regulation activities.Structure-activity relationship studies showed that Elai occupied the binding pocket with several key interactions.Furthermore,Elai markedly reduced the recruitment of RORγto its genomic DNA response element(RORE),suppressed the expression of RORγtarget 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 RORγinhibitor that can be used as a drug candidate for the treatment of human CRPC.