For a promising preclinical compound, serious toxicities were observed during in-vivo testing. These included lung hemorrhages and hematological abnormalities, decrease in hematopoietic cells, hypersegmentation and vacuolation in myeloid cells. It was however unknown which molecular events were causing the toxic reaction. The molecular pathway leading to these toxicities is unknown, and could result from both on-target or off-target effects which are all assessed as part of the project.

The customer set up an internal project to do a differential analysis on the data. This was mainly literature based, and this initial literature study did not provide any obvious answers.

“The proposed mechanism of action was very attractive. The Euretos team helped to explain the phenomenon as it was observed in mouse studies. We are very grateful for this report which has provided us with a lot of very useful information.”

Principal Scientist,Large Japanese Pharma

We used a data driven approach which enabled us to understand the underlying dysregulated biological process. We started by performing a similarity search with the expression signature induced by compound to identify similar gene expression signatures and the causing agents. We then performed cell type deconvolution, which suggested a decrease in microvascular endothelial cells in the affected lung tissue. Combining these two outcomes, we did a signaling network analysis, where we ranked different transcription factors and receptors and were able to identify the most influential receptors.

We identified one specific target which could explain all observations. Our conclusion was instantly corroborated by the customer as they revealed that this target had one of the highest affinity levels with the compound. Now that the specific toxicity causing ‘off target’ effect was known, the customer was able to select another compound which was also efficacious which avoided the toxicity pathway.