A novel steroidal inhibitor of estrogen-related receptor α (ERRα)

The orphan nuclear receptor estrogen-related receptor alpha (ERR alpha) has been implicated in the development of various human malignancies, including breast, prostate, ovary, and colon cancer ERR alpha, bound to a coactivator protein (e g. peroxisome proliferator receptor gamma co-activator-l alpha, PGC-1 alpha). regulates cellular energy metabolism by activating transcription of genes involved in various metabolic processes, such as mitochondrial genesis, oxidative phosphorylation, and fatty acid oxidation. Accumulating evidence suggests that ERR alpha is a novel target for solid tumor therapy, conceivably through effects on the regulation of tumor cell energy metabolism associated with energy stress within solid tumor microenvironments This report describes a novel steroidal antiestrogen (SR16388) that binds selectively to ERR alpha, but not to ERR beta or ERR gamma, as determined using a time-resolved fluorescence resonance energy transfer assay SR16388 potently inhibits ERR alpha's transcriptional activity in reporter gene assays, and prevents endogenous PGC-1 alpha and ERR alpha from being recruited to the promoters or enhancers of target genes Representative in vivo results show that SR16388 inhibited the growth of human prostate tumor xenografts in nude mice as a single agent at 30 mg/kg given once daily and 100 mg/kg given once weekly In a combination study, SR16388 (10 mg/kg, once daily) and pachtaxel (7 5 mg/kg, twice weekly) inhibited the growth of prostate tumor xenografts in nude mice by 61% compared to untreated xenograft tumors. SR 16388 also inhibited the proliferation of diverse human tumor cell lines after a 24-h exposure to the compound. SRI 6388 thus has utility both as an experimental antitumor agent and as a chemical probe of ERRcx biology. (C) 2010 Elsevier Inc All rights reserved