Characterization of a selective inverse agonist for estrogen related receptor α as a potential agent for breast cancer

The estrogen-related receptor alpha (ERR alpha) is an orphan nuclear receptor that plays a primary role in the regulation of cellular energy homeostasis and osteogenesis. It is reported that ERR alpha is widely expressed in a range of tissues and accumulating evidence has supported that the high expression of ERR alpha 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 ERR alpha, but not of ERR beta and ERR gamma, as determined using transient transfection luciferase reporter assay and a time-resolved fluorescence resonance energy transfer (TR-FRET) co-activator assay. HSP1604 potently inhibits ERR alpha transcriptional activity with IC50=1.47 +/- 0.17 mu M in cell-based luciferase reporter assay and also decreases the protein level of ERR alpha 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 ERR alpha. Representative in vivo results show that HSP1604 suppresses the growth of human breast cancer xenograft in nude mice as doses at 30 mg/kg or 100 mg/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 ERR alpha biology. (C) 2016 Elsevier B.V. All rights reserved.