Image-based phenotypic profiling of a chemogenomic screening library identifies novel druggable targets in the EGFR-pathway
Image-based phenotypic profiling of a chemogenomic screening library identifies novel druggable targets in the EGFR-pathway
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DOI：
10.1101/2021.04.16.440090
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发表时间：
2021-04
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影响因子：
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通讯作者：
K. Tanabe
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作者：
K. Tanabe
编码表皮生长因子受体（EGFR）的基因是癌症中的主要驱动基因。已经开发了许多靶向EGFR相关分子的药物，但由于缺乏疗效和/或意外的副作用，许多药物在临床试验中失败。在这项研究中，我使用基于图像的表型分析来筛选具有生物活性的化合物库，目的是在EGFR通路中识别新的可药用靶点。如预期的，表型筛选鉴定了产生由靶向已知特定分子或途径产生的表型的化合物。该试验还表明，具有不同已知作用机制的化合物产生相似的EGFR相关细胞表型。生物化学分析显示，这些化合物具有以前未被认识到的共同靶标/途径，表明基于图像的分析可以识别独立于化合物已知靶标的新靶分子。进一步的实验表明，ROCK 1和PSMD 2是EGFR通路中的新的可药物化靶点。
The gene encoding epidermal growth factor receptor (EGFR) is a major driver gene in cancer. Many drugs targeting EGFR-associated molecules have been developed, yet many have failed in clinical trials due to a lack of efficacy and/or unexpected side effects. In this study, I used image-based phenotypic profiling to screen a pharmacologically active compound library with the aim of identifying new druggable targets in the EGFR pathway. As anticipated, the phenotypic screen identified compounds that produce phenotypes resulting from targeting a known specific molecule or pathway. The assay also showed that compounds with diverse known mechanisms of action produced similar, EGFR-related cellular phenotypes. Biochemical assays revealed that those compounds share a previously unappreciated common target/pathway, showing that the image-based assay can identify new target molecules that are independent of the compound’s known target. Further experiments showed that ROCK1 and PSMD2 are novel druggable targets within the EGFR pathway.