The discovery of novel, potent ERR-alpha inverse agonists for the treatment of triple negative breast cancer

• DOI: 10.1016/j.ejmech.2017.04.050
• Publication Date: 2017-04-22T10:46:34Z
• Authors: Yongli Du; Lianhua Song; Liudi Zhang; Hao Ling; Yanhui Zhang; Haifei Chen; Huijie Qi; Xiaojin Shi; Qunyi Li
• Keywords: ERRalpha Estrogen-Related Receptor; 0303 health sciences; Dose-Response Relationship, Drug; Molecular Structure; Antineoplastic Agents; Triple Negative Breast Neoplasms; 3. Good health; Structure-Activity Relationship; Thiazoles; 03 medical and health sciences; Receptors, Estrogen; Cell Line, Tumor; Drug Discovery; Nitriles; Humans; Female; Drug Screening Assays, Antitumor; Cell Proliferation

The estrogen-related receptor α (ERRα) is an orphan receptor and 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 micro environments. Here we describe the discovery of novel potent inverse agonists of ERRα. In vitro, compound 11 potently inhibits ERRα's transcriptional activity by preventing endogenous PGC-1α and ERRα binding and suppresses the proliferation of different human cancer cell lines and the migration of breast cancer cells (MDA-MB-231). In vivo, compound 11 demonstrates a strong inhibitory effect on the growth of human breast cancer xenografts (MDA-MB-231) and the tumor growth is inhibited by 40.9% after treating with compound 11 (30 mg/kg). The binding mode shows that compound 11 interacts with the binding pocket of ERRα through hydrogen interactions with the residue Gly397 and hydrophobic interactions with the hydrophobic residues. All these results suggest that compound 11 represents a novel potent ERRα inverse agonist and is promising in the discovery of antitumor compounds for the treatment of triple negative breast cancer.