National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
Cell Chem Biol. 2021 Mar 18;28(3):356-370. doi: 10.1016/j.chembiol.2021.01.021. Epub 2021 Feb 15.
Compounds that exhibit assay interference or undesirable mechanisms of bioactivity ("nuisance compounds") are routinely encountered in cellular assays, including phenotypic and high-content screening assays. Much is known regarding compound-dependent assay interferences in cell-free assays. However, despite the essential role of cellular assays in chemical biology and drug discovery, there is considerably less known about nuisance compounds in more complex cell-based assays. In our view, a major obstacle to realizing the full potential of chemical biology will not just be difficult-to-drug targets or even the sheer number of targets, but rather nuisance compounds, due to their ability to waste significant resources and erode scientific trust. In this review, we summarize our collective academic, government, and industry experiences regarding cellular nuisance compounds. We describe assay design strategies to mitigate the impact of nuisance compounds and suggest best practices to efficiently address these compounds in complex biological settings.
在细胞测定中，包括表型和高内涵筛选测定，经常会遇到表现出测定干扰或不良生物活性机制的化合物（“麻烦化合物”）。在无细胞测定中，人们对化合物依赖性测定干扰已经有了很多了解。然而，尽管细胞测定在化学生物学和药物发现中起着至关重要的作用，但在更复杂的基于细胞的测定中，对麻烦化合物的了解要少得多。在我们看来，实现化学生物学全部潜力的主要障碍不仅是难以成药的靶标，甚至不是靶标的数量，而是麻烦化合物，因为它们有能力浪费大量资源并侵蚀科学信任。在这篇综述中，我们总结了我们在学术、政府和工业界方面有关细胞麻烦化合物的集体经验。我们描述了减轻麻烦化合物影响的测定设计策略，并提出了在复杂生物环境中有效处理这些化合物的最佳实践。
