TOPIC

Combining target based and phenotypic approaches to enhance early safety profiling and prediction of drug-induced cardiotoxicity

Journal

ICMS 2024 UK

Author(s)

David Standing

Year

2024

Off-target cardiac effects are commonly assessed in early stage drug discovery using a panel of target specific assays for human cardiac ion channels (e.g. hERG, NaV1.5, CaV1.2). However, these assays are focussed on acute arrhythmia-inducing compounds (i.e. only a small proportion of cardiotoxicants) and do not identify other mechanisms of cardiotoxicity. In addition, most safety failures are due to preclinical toxicities and therefore early safety screening against the most appropriate cell types is also desirable. Assays using human induced pluripotent stem cell-derived cardiomyocytes (hiPSc-CM) on a variety of platforms (multi electrode array (MEA), manual patch clamp) can be used to address these gaps. As well as screening a panel of human cardiac ion channels on the Qube, we have deployed a high throughput Cardio-Motion Assay- a phenotypic screen utilizing imaging of (hiPSc-CM)- to measure changes in beating characteristics which may be due to compound-induced structural and functional effects.

Here we describe both target based and phenotypic assays and compare their outputs to demonstrate an enhanced ability to identify potential cardiotoxicity.

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