1-Phenyl-4-benzoyl-1H-1,2,3-triazoles as Orally Bioavailable Transcriptional Function Suppressors of Estrogen-Related Receptor α
1-Phenyl-4-benzoyl-1H-1,2,3-triazoles as Orally Bioavailable Transcriptional Function Suppressors of Estrogen-Related Receptor α
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DOI：
10.1021/jm4003928
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发表时间：
2013-06-13
影响因子：
7.3
通讯作者：
Ding, Ke
中科院分区：
文献类型：
--
作者：
Xu, Shilin;Zhuang, Xiaoxi;Ding, Ke
雌激素相关受体a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-1H-1，2，3-三唑作为ERR α转录功能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）-1H-1，2，3-三唑-4-基）甲酮（14 n）在基于细胞的报告基因测定中有效抑制ERR α的转录功能，IC 50 = 0.021 μ M，并且还降低ERR α和下游靶标的mRNA水平和蛋白水平。该化合物抑制具有高水平ERR α的乳腺癌细胞的增殖和迁移。初步的药代动力学研究表明，它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的小分子探针，用于进一步验证ERR α作为抗癌药物开发的分子靶点。
Estrogen-related receptor a 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 ERR alpha transcriptional functions. The most promising compound, 2-aminophenyl-(1-(3-isopropylpheny1)-1H-1,2,3-triazol-4-yl)methanone (14n), potently suppressed the transcriptional functions of ERR alpha with IC50 = 0.021 mu M in a cell-based reporter gene assay and also decreased both the mRNA levels and the protein levels of ERR alpha and the downstream targets. This compound inhibited the proliferation and migration of breast cancer cells with high level of ERR alpha. Preliminary pharmacolcinetic 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 ERR alpha as a molecular target for anticancer drug development.