Du Yongli, Song Lianhua, Zhang Liudi, Ling Hao, Zhang Yanhui, Chen Haifei, Qi Huijie, Shi Xiaojin, Li Qunyi
School of Chemistry and Pharmaceutical Engineering, Qilu University of Technology, 3501 Daxue Road, Jinan 250353, China.
School of Chemistry and Pharmaceutical Engineering, Qilu University of Technology, 3501 Daxue Road, Jinan 250353, China.
Eur J Med Chem. 2017 Aug 18;136:457-467. doi: 10.1016/j.ejmech.2017.04.050. Epub 2017 Apr 22.
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.
雌激素相关受体α（ERRα）是一种孤儿受体，也是实体瘤治疗的新靶点，可能是通过影响实体瘤微环境中与能量应激相关的肿瘤细胞能量代谢调节来实现的。在此，我们描述了新型强效ERRα反向激动剂的发现。在体外，化合物11通过阻止内源性PGC-1α与ERRα结合，有效抑制ERRα的转录活性，并抑制不同人类癌细胞系的增殖以及乳腺癌细胞（MDA-MB-231）的迁移。在体内，化合物11对人乳腺癌异种移植瘤（MDA-MB-231）的生长具有强烈抑制作用，用化合物11（30mg/kg）处理后肿瘤生长被抑制了40.9%。结合模式表明，化合物11通过与残基Gly397的氢键相互作用以及与疏水残基的疏水相互作用，与ERRα的结合口袋相互作用。所有这些结果表明，化合物11是一种新型强效ERRα反向激动剂，在发现用于治疗三阴性乳腺癌的抗肿瘤化合物方面具有前景。
