Tales of 1,008 small molecules: phenomic profiling through live-cell imaging in a panel of reporter cell lines

Tales of 1,008 small molecules: phenomic profiling through live-cell imaging in a panel of reporter cell lines

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) predict...

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Bibliographic Details
Published in:Scientific reports Vol. 10; no. 1; p. 13262
Main Authors: Cox, Michael J., Jaensch, Steffen, Van de Waeter, Jelle, Cougnaud, Laure, Seynaeve, Daan, Benalla, Soulaiman, Koo, Seong Joo, Van Den Wyngaert, Ilse, Neefs, Jean-Marc, Malkov, Dmitry, Bittremieux, Mart, Steemans, Margino, Peeters, Pieter J., Wegner, Jörg Kurt, Ceulemans, Hugo, Gustin, Emmanuel, Chong, Yolanda T., Göhlmann, Hinrich W. H.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 06-08-2020
Nature Publishing Group
Subjects:
631/154
631/154/1435/2417
631/92/613
692/308/153
A549 Cells
Annotations
Biological Products - pharmacology
Cell Line
Cell lines
Drug Discovery
Fluorescent indicators
Gene expression
Gene Expression Regulation - drug effects
Hep G2 Cells
Humanities and Social Sciences
Humans
Luminescent Proteins - genetics
Luminescent Proteins - metabolism
Microscopy
Morphology
multidisciplinary
Natural products
Phenomics - methods
Proteins
Science
Science (multidisciplinary)
Small Molecule Libraries - pharmacology
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Description
Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-020-69354-8