title: Characterization of a selective inverse agonist for estrogen related receptor α as a potential agent for breast cancer.
abstract: The estrogen-related receptor α (ERRα) is an orphan nuclear receptor that plays a primary role in the regulation of cellular energy homeostasis and osteogenesis. It is reported that ERRα is widely expressed in a range of tissues and accumulating evidence has supported that the high expression of ERRα correlates with poor prognosis of various human malignancies, including breast, endometrium, colon, prostate and ovary cancers. Herein is described the discovery of a novel selective inverse agonist (HSP1604) of ERRα, but not of ERRβ and ERRγ, as determined using transient transfection luciferase reporter assay and a time-resolved fluorescence resonance energy transfer (TR-FRET) co-activator assay. HSP1604 potently inhibits ERRα transcriptional activity with IC50=1.47±0.17μM in cell-based luciferase reporter assay and also decreases the protein level of ERRα and the mRNA levels of its downstream target genes such as pyruvate dehydrogenase kinase 4 (PDK4), pS2 and osteopontin. HSP1604 has also suppressed the proliferation of different human cancer cell lines and the migration of breast cancer cells with high expression of ERRα. Representative in vivo results show that HSP1604 suppresses the growth of human breast cancer xenograft in nude mice as doses at 30mg/kg or 100mg/kg administered every other day during 28-day period. HSP1604 thus has the potential both as a new agent to inhibit the growth of tumors and as a chemical probe of ERRα biology.
authors: Clinical Pharmacy Laboratory, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors: Liudi
authors: L
authors: Zhang
authors: School of Chemistry and Pharmaceutical Engineering, Qilu University of Technology, Jinan 250353, China.
authors: Peihong
authors: P
authors: Liu
authors: Clinical Pharmacy Unit, Huashan Hospital North, Fudan University, Shanghai 201907, China.
authors: Haifei
authors: H
authors: Chen
authors: Clinical Pharmacy Laboratory, Huashan Hospital, Fudan University, Shanghai 200040, China; Clinical Pharmacy Unit, Huashan Hospital North, Fudan University, Shanghai 201907, China. Electronic address: qyli1234@163.com.
authors: Qunyi
authors: Q
authors: Li
authors: Clinical Pharmacy Unit, Huashan Hospital North, Fudan University, Shanghai 201907, China.
authors: Lu
authors: L
authors: Chen
authors: Clinical Pharmacy Unit, Huashan Hospital North, Fudan University, Shanghai 201907, China.
authors: Huijie
authors: H
authors: Qi
authors: Clinical Pharmacy Laboratory, Huashan Hospital, Fudan University, Shanghai 200040, China; Clinical Pharmacy Unit, Huashan Hospital North, Fudan University, Shanghai 201907, China.
authors: Xiaojin
authors: X
authors: Shi
authors: School of Chemistry and Pharmaceutical Engineering, Qilu University of Technology, Jinan 250353, China. Electronic address: ylduyjs@163.com.
authors: Yongli
authors: Y
authors: Du
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D054314:Drug Inverse Agonism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D059748:Proteolysis / Q000187:drug effects; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D000970:Antineoplastic Agents; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor
keywords: Antitumor agent; Breast cancer xenograft; Estrogen related receptor α; Inverse agonist; Migration; Proliferation