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Updated: Apr 4, 2026
Author Spotlight: Cost-Effective Transcriptomic Drug Screening - Unlocking New Targets
Published on: February 23, 2024
Integrating High-Dimensional Transcriptomics and Image Analysis Tools into Early Safety Screening: Proof of Concept
Bie M P Verbist1, Geert R Verheyen1, Liesbet Vervoort1
1Janssen R&D , Turnhoutseweg 30, 2340 Beerse, Belgium.
Abstract:
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 ability of animal models to predict the human situation, modern unbiased high-dimensional biology readouts are sought, such as molecular signatures predictive for 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 analogues that commonly downregulate multiple 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 initial 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 that 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.
Insights
Early drug toxicity screening using transcriptional profiling can identify potential spindle poisons and genotoxic compounds, reducing late-stage failures. This approach leverages existing exploratory data for safety assessment in drug development.
Area of Science:
- Drug Discovery and Development
- Toxicology
- Genomics
Background:
- Late-stage drug development failures are costly, often due to unforeseen adverse effects.
- Current animal models have limitations in predicting human responses to drug toxicity.
- There is a need for early, unbiased methods to identify potential drug toxicity using high-dimensional biological readouts.
Purpose of the Study:
- To demonstrate a proof of concept for early toxicity flagging in drug discovery.
- To explore the potential of transcriptional profiling for identifying adverse effects.
- To integrate exploratory experimental data into safety assessment strategies.
Main Methods:
- Transcriptional profiling of chemical analogues to identify molecular signatures.
- In vitro micronucleus tests for genotoxicity assessment.
- High-content imaging to identify cellular phenotypes like aggregate formation.
- Structure-Activity Relationship (SAR) analysis to guide compound synthesis.
Main Results:
- Identified a subset of analogues downregulating tubulin genes, suggesting spindle poison activity.
- Confirmed genotoxic effects using the in vitro micronucleus test.
- Observed characteristic aggregate formation via high-content imaging.
- Extended the series of compounds exhibiting genotoxic effects through SAR analysis.
Conclusions:
- Early identification of toxicity is feasible using transcriptional profiling and other exploratory data.
- This approach can flag potential safety issues, such as genotoxicity and spindle poison effects, early in drug discovery.
- Integrating such analyses into standard workflows can improve drug development efficiency and reduce late-stage attrition.
