摘要

Unlike other breast cancer subtypes, targeted therapies for triple negative breast cancer (TNBC) have yet to progress past clinical trial stage to approval. Accumulating evidences demonstrated that expression of estrogen-related receptor alpha (ERR alpha) indicated worse prognosis and correlated with poor outcome in breast cancers including TNBC. Therefore, ERR alpha modulators/regulators may be potential in the therapeutic treatment of breast cancers. In the current study, we presented a novel compound LingH2-10 that bound to ERR alpha, as identified using a time-resolved fluorescence resonance energy transfer assay (TR-FRET) with the IC50 value of 0.64 +/- 0.12 mu M. Further, functional activity was determined by transient transfection luciferase reporter assay in order to validate the utility of the binding affinity in a cellular context. LingH2-10 showed selective inhibition on ERR alpha transcriptional activity with the IC50 value of 0.58 +/- 0.09 mu M in cell-based luciferase reporter assay. Moreover, representative in vitro results showed that LingH2-10 suppressed the proliferation of various human cancer cells, and inhibited the migration of triple negative breast cancer cell MDA-MB-231. In addition, our results demonstrated that well known ERR alpha target genes such as PDK4, Osteopontin and pS2, were all significantly down modulated by LingH2-10. In vivo experiments showed that LingH2-10 (30 mg/kg, every other day) observably suppressed the growth of MDA-MB-231 xenograft tumors by 42.02% compared to untreated xenograft tumors. Taken together, all these data suggested that LingH2-10, as a selective inverse agonist of ERR alpha, was a lead compound of anti-cancer agents for treating TNBC patients.