Assessing the biological activity of compounds is an essential objective of biomedical research. We show that one can infer the bioactivity of compounds by assessing the activity of transcription factors (TFs) that regulate gene expression. Using a multiplex reporter system, the FACTORIAL, we characterized cell response to a compound by a quantitative signature, the TF activity profile (TFAP). We found that perturbagens of biological pathways elicited distinct TFAP signatures in human cells. Unexpectedly, perturbagens of the same pathway all produced identical TFAPs, regardless of where or how they interfered. We found invariant TFAPs for mitochondrial, histone deacetylase, and ubiquitin/proteasome pathway inhibitors; cytoskeleton disruptors; and DNA-damaging agents. Using these invariant signatures permitted straightforward identification of compounds with specified bioactivities among uncharacterized chemicals. Furthermore, this approach allowed us to assess the multiple bioactivities of polypharmacological drugs. Thus, TF activity profiling affords straightforward assessment of the bioactivity of compounds through the identification of perturbed biological pathways.

中文翻译：

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通过转录因子活性分析评估化合物的生物学活性。

评估化合物的生物活性是生物医学研究的基本目标。我们表明，可以通过评估调节基因表达的转录因子（TFs）的活性来推断化合物的生物活性。使用多重报告系统FACTORIAL，我们通过定量标记TF活性谱（TFAP）表征了细胞对化合物的反应。我们发现生物通路的扰动在人类细胞中引起不同的TFAP签名。出乎意料的是，相同路径的扰动都产生相同的TFAP，无论它们在何处或如何进行干扰。我们发现线粒体，组蛋白脱乙酰基酶和泛素/蛋白酶体途径抑制剂的不变TFAPs。细胞骨架干扰物；和DNA破坏剂。使用这些不变的特征可以在未表征的化学药品中直接鉴定具有特定生物活性的化合物。此外，这种方法使我们能够评估多药理学药物的多种生物活性。因此，TF活性分析通过鉴定受干扰的生物途径，提供了化合物生物活性的直接评估。