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首页> 外文期刊>Journal of biomolecular screening: The official journal of the Society for Biomolecular Screening >Phenotype-based screening of mechanistically annotated compounds in combination with gene expression and pathway analysis identifies candidate drug targets in a human squamous carcinoma cell model
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Phenotype-based screening of mechanistically annotated compounds in combination with gene expression and pathway analysis identifies candidate drug targets in a human squamous carcinoma cell model

机译：基于表型的机械注释化合物筛选与基因表达和途径分析相结合，可鉴定人鳞状癌细胞模型中的候选药物靶标

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摘要

The squamous cell carcinoma HeLa cell line and an epithelial cell line hTERT-RPE with a nonmalignant phenotype were interrogated for HeLa cell selectivity in response to 1267 annotated compounds representing 56 pharmacological classes. Selective cytotoxic activity was observed for 14 of these compounds dominated by cyclic adenosine monophosphate (cAMP) selective phosphodiesterase (PDE) inhibitors, which tended to span a representation of the chemical descriptor space of the library. The PDE inhibitors induced delayed cell death with features compatible with classical apoptosis. The PDE inhibitors were largely inactive when tested against a cell line panel consisting of hematological and nonsquamous epithelial phenotypes. In a genome-wide DNA microarray analysis, PDE3A and PDE2A were found to be significantly increased in HeLa cells compared to the other cell lines. The pathway analysis software PathwayAssist was subsequently used to extract a list of proteins and small molecules retrieved from Medline abstracts associated with the hit compounds. The resulting list consisted of major parts of the cAMP-protein kinase A pathway linking to ERK, P38, and AKT. This molecular network may provide a basis for further exploitation of novel candidate targets for the treatment of squamous cell carcinoma.
机译：响应于代表56种药理学类别的1267种带注释化合物，对鳞状细胞癌HeLa细胞系和具有非恶性表型的上皮细胞系hTERT-RPE询问了HeLa细胞的选择性。这些化合物中有14种被环状单磷酸腺苷（cAMP）选择性磷酸二酯酶（PDE）抑制剂所控制，具有选择性的细胞毒活性，该活性倾向于跨越文库化学描述符空间的表示。 PDE抑制剂可诱导延迟性细胞死亡，其功能与经典细胞凋亡兼容。当针对由血液学和非鳞状上皮表型组成的细胞系测试时，PDE抑制剂大部分没有活性。在全基因组DNA微阵列分析中，与其他细胞系相比，发现HeLa细胞中PDE3A和PDE2A显着增加。随后使用路径分析软件PathwayAssist提取了从与命中化合物相关的Medline摘要中检索到的蛋白质和小分子的列表。结果列表由连接到ERK，P38和AKT的cAMP-蛋白激酶A通路的主要部分组成。该分子网络可为进一步开发用于治疗鳞状细胞癌的新候选靶标提供基础。

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