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 ...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.展开更多
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)+5 种基金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)
文摘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.
