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

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

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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 RORγ as a novel therapeutic target for CRPC.Here,we reveal that elaiophylin(Elai),an antibiotic from Actinomycete streptomyces,is a novel RORγ antagonist and showed potent antitumor ac-tivity against CRPC in vitro and in vivo.We demonstrated that Elai selectively binded to RORγ protein and potently blocked RORy 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 RORy to its genomic DNA response element(RORE),suppressed the expres-sion 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 RORy inhibitor that can be used as a drug candidate for the treatment of human CRPC.

RORyCastration-resistant prostate cancerNuclear receptorAntagonistElaiophylin

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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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

Department of Biochemistry and Molecular Medicine,UC Davis Comprehensive Cancer Center,School of Medicine,University of California,Davis,Sacramento,CA 95817,USA

Department of Urology,the SecondAffiliated Hospital of Guangzhou University of Chinese Medicine,Guangzhou 510120,China

Department of Joint Orthopaedic,the First Affiliated Hospital,Guangzhou University of Chinese Medicine,Guangzhou 510405,China

National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation,Sun Yat-sen University,Guangzhou 510006,China

Guangdong Provincial Key Laboratory of New Drug Design and Evaluation,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China

Department of Gastrointestinal Surgery,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510120 China

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National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaGuangdong Natural Science Funds for Distin-guished Young ScholarGuangdong Natural Science Funds for Distin-guished Young ScholarSci-ence and Technology Planning Project of Guangdong ProvinceSci-ence and Technology Planning Project of Guangdong ProvinceLocal Innovative and Research Teams Project of Guangdong Pearl River Talents ProgramLocal Innovative and Research Teams Project of Guangdong Pearl River Talents ProgramNational Major Special Projects for the Creation and Manufacture of New DrugsNational Major Special Projects for the Creation and Manufacture of New DrugsNational Engineering and Technology Research Center for New drug Druggability EvaluationNational Engineering and Technology Research Center for New drug Druggability EvaluationNational Engineering and Technology Research Center for New drug Druggability EvaluationFundamental Research Funds for the Central UniversitiesFundamental Research Funds for the Central UniversitiesPearl River S&T Nova Program of GuangzhouPearl River S&T Nova Program of Guangzhou

818728918157292581774339417761692019B151502016China2017A050506042China2017BT01Y093China2019ZX09301104ChinaSeed Program of Guangdong Province2017B090903004China19ykzd23China201710010136China

2020

药学学报(英文版)

药学学报(英文版)

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ISSN：
年,卷(期)：2020.10(12)
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