Estrogen-related receptor α is a potential candidate target for therapeutic treatment of breast cancer. We describe the discovery and structure–activity relationship study of a series of 1-phenyl-4-benzoyl-1H-1,2,3-triazoles as novel suppressors of ERRα transcriptional functions. The most promising compound, 2-aminophenyl-(1-(3-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone (14n), potently suppressed the transcriptional functions of ERRα with IC₅₀ = 0.021 μM in a cell-based reporter gene assay and also decreased both the mRNA levels and the protein levels of ERRα and the downstream targets. This compound inhibited the proliferation and migration of breast cancer cells with high level of ERRα. Preliminary pharmacokinetic studies suggested that it possessed a good pharmacokinetic profile with an oral bioavailability of 71.8%. The compounds may serve as novel small molecule probes for further validation of ERRα as a molecular target for anticancer drug development.

中文翻译：

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1-苯基-4-苯甲酰基-1H-1,2,3-三唑作为雌激素相关受体α的口服生物利用转录功能抑制剂


雌激素相关受体α是乳腺癌治疗的潜在候选靶点。我们描述了一系列 1-苯基-4-苯甲酰基-1 H -1,2,3-三唑作为 ERRα 转录功能的新型抑制剂的发现和构效关系研究。最有前途的化合物，2-氨基苯基-(1-(3-异丙基苯基)-1 H -1,2,3-三唑-4-基)甲酮 ( 14n )，可有效抑制 ERRα 的转录功能，IC ₅₀ = 0.021 μM 在基于细胞的报告基因测定中也降低了 ERRα 和下游靶标的 mRNA 水平和蛋白质水平。该化合物抑制高水平 ERRα 的乳腺癌细胞的增殖和迁移。初步药代动力学研究表明其具有良好的药代动力学特征，口服生物利用度为71.8%。这些化合物可以作为新型小分子探针，进一步验证 ERRα 作为抗癌药物开发的分子靶点。