The estrogen-related receptor alpha (ERR alpha) 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 ERR alpha. In vitro, compound 11 potently inhibits ERR alpha's transcriptional activity by preventing endogenous PGC-1 alpha and ERR alpha 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 ERR alpha 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 ERR alpha inverse agonist and is promising in the discovery of antitumor compounds for the treatment of triple negative breast cancer. (C) 2017 Published by Elsevier Masson SAS.
[1]Qilu Univ Technol, Sch Chem & Pharmaceut Engn, 3501 Daxue Rd, Jinan 250353, Peoples R China.
[2]Fudan Univ, Huashan Hosp North, Dept Pharm, 108 Luxiang Rd, Shanghai 201907, Peoples R China.
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