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E-GEOD-70611 - Integrating high-dimensional transcriptomics and image analysis tools into early safety screening (I)

Status
Released on 31 December 2015, last updated on 2 January 2016
Organism
Homo sapiens
Samples (4)
Array (1)
Protocols (7)
Description
In this paper we demonstrated the potential to flag toxicity issues by utilizing data from exploratory experiments which are typically generated for target evaluation purposes during early drug discovery During drug discovery and development, the early identification of adverse effects is expected to reduce costly late stage failures of candidate drugs. As risk/safety assessment takes place rather late during the development process and due to the limited predictivity of animal models to the human situation, modern unbiased high-dimensional biology read-outs are sought, such as molecular signatures of in vivo response using high-throughput cell-based assays. In this theoretical proof-of-concept we provide findings of an in-depth exploration of a single chemical core structure. Via transcriptional profiling we identified a subset of close analogs which commonly down-regulate tubulin genes across cellular contexts, suggesting possible spindle poison effects. Confirmation via a qualified toxicity assay (in vitro micronucleus test) and the identification of a characteristic aggregate-formation phenotype via exploratory high content imaging validated the inititial findings. SAR analysis triggered the synthesis of a new set of compounds and allowed us to extend the series showing the genotoxic effect. We demonstrate the potential to flag toxicity issues by utilizing data from exploratory experiments which are typically generated for target evaluation purposes during early drug discovery. We share our thoughts on how this approach may be incorporated into drug development strategies. Cells were cultured using standard protocols, seeded in 96 well plate, cultured for 8 hours before treatment with a number of inhouse synthesized compounds. The treatments represent different chemical structures/small molecules that have been synthesized in the context of developing a new drug targeting PDE10A.
Experiment type
transcription profiling by array 
Contacts
Steven Osselaer <sosselae@its.jnj.com>, Bie M Verbist, Cindy Bosmans, Dirk Wuyts, Dominiek Beerens, Freddy Van Goethem, Geert R Verheyen, Geert Van Hecke, Hinrich Göhlmann, Ilse Van den Wyngaert, Liesbet Vervoort, Marjolein Crabbe, Steffen Jaensch, Willem Talloen
MIAME
PlatformsProtocolsVariablesProcessedRaw
Files
Investigation descriptionE-GEOD-70611.idf.txt
Sample and data relationshipE-GEOD-70611.sdrf.txt
Raw data (1)E-GEOD-70611.raw.1.zip
Processed data (1)E-GEOD-70611.processed.1.zip
Array designA-GEOD-19100.adf.txt
Links