Automated Tyrosine Kinase Inhibitor Cardiotoxicity Assay in Zebrafish

Abstract

The zebrafish embryos have recently gained relevance in biomedical research thanks to some of its characteristics including embryo transparency, small size, ease of manipulation and possibility to evaluate different internal organs avoiding invasive methodologies. Combined with the possibility to adapt the model with an automatic device and the reduced cost associated to each assay, the model is an ideal killer experiment in early phases of drug discovery as well as a novel method to increase the selection arguments to reduce the candidates to enter into the Drug Development process.

Cardiotoxicity is one of the most important reasons for drug attrition during the process of Drug Development. Evaluation of cardiotoxicity and especially HERG channel inhibition is described in regulatory guidelines, but limitations demands the development of new complimentary assays that can also evaluate the heart function from a histolic point of view. Biobide has set up a novel in vivo automated platform that allows testing compounds in zebrafish embryos.

To evaluate and validate the quality of the analysis system, the model and the value of the information, we have used a panel of blind-coded Tyrosine kinase inhibitors that had been previously described in other in vitro and in vivo assays. The results indicate that our automated method provides with high informative and complementary data that can significantly improve the process of selection of new candidates with low or no cardiotoxicity.