Tales of 1,008 Small Molecules: Phenomic Profiling through Live-cell Imaging in a Panel of Reporter Cell Lines
| Autor: | Laure Cougnaud, Hugo Ceulemans, Seong Joo Koo, Jelle Van de Waeter, Jean-Marc Neefs, Emmanuel Gustin, Jörg K. Wegner, Hinrich W. H. Göhlmann, Margino Steemans, Ilse Van den Wyngaert, Michael J. Cox, Soulaiman Benalla, Steffen Jaensch, Pieter J. Peeters, Yolanda T. Chong, Daan Seynaeve, Dmitry Malkov, Mart Bittremieux |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Phenotypic screening lcsh:Medicine Drug development Computational biology Biology Article Cell Line Small Molecule Libraries 03 medical and health sciences 0302 clinical medicine Live cell imaging Profiling (information science) Humans Phenomics lcsh:Science Biological Products Multidisciplinary Drug discovery Small molecules lcsh:R Hep G2 Cells Small molecule Luminescent Proteins 030104 developmental biology Gene Expression Regulation Cell culture A549 Cells lcsh:Q 030217 neurology & neurosurgery |
| Zdroj: | Scientific Reports, Vol 10, Iss 1, Pp 1-14 (2020) Scientific Reports |
| DOI: | 10.1101/2020.03.13.990093 |
| Popis: | Phenomic profiles are high-dimensional sets of readouts that can comprehensively capture the biological impact of chemical and genetic perturbations in cellular assay systems. Phenomic profiling of compound libraries can be used for compound target identification or mechanism of action (MoA) prediction and other applications in drug discovery. To devise an economical set of phenomic profiling assays, we assembled a library of 1,008 approved drugs and well-characterized tool compounds manually annotated to 218 unique MoAs, and we profiled each compound at four concentrations in live-cell, high-content imaging screens against a panel of 15 reporter cell lines, which expressed a diverse set of fluorescent organelle and pathway markers in three distinct cell lineages. For 41 of 83 testable MoAs, phenomic profiles accurately ranked the reference compounds (AUC-ROC ≥ 0.9). MoAs could be better resolved by screening compounds at multiple concentrations than by including replicates at a single concentration. Screening additional cell lineages and fluorescent markers increased the number of distinguishable MoAs but this effect quickly plateaued. There remains a substantial number of MoAs that were hard to distinguish from others under the current study’s conditions. We discuss ways to close this gap, which will inform the design of future phenomic profiling efforts. |
| Databáze: | OpenAIRE |
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