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Kinase study of cytotoxicity voted paper of the year.

Jun 6, 2018

Use of kinase inhibitors (KI) for therapeutic purposes is limited by their cardiotoxicity. Therefore, further design of new KIs further understanding is required. In the human genome there are over 500 kinases present. The binding site for ATP is quite conserved between them creating polypharmacology. Because kinases show flexibility in binding across the kinome, researchers in this study have assesed the effects on cardomyocyte beating. After this high throuhput analysis 30 of the inicial 65 kinases were deemed to have met the criteria of having pharmacological inhibition, expression in both human induced pluripotent stem cell-derived cardiomyocytes and adult heart tissue, and effect on cardomyocyte beating following single gene knockdown. These kinases were then chosen for a mechanistic study.
The xCELLigence system was used to predict cytotoxicity hazards in the study. To quote:

"Impedance-based assays with hiPSC CM have proven highly predictive for each of the leading functional cardiotoxicity hazards including arrhythmia (hERG and non-hERG related), chronotropy, inotropy, and KI induced functional cardiotoxicity"

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Agilent technologies

Agilent provides xCELLigence impedance-based, label-free, real time cell analysis system and NovoCyte flow cytometers.

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The RTCA DP Analyzer has three integrated stations for E-Plates 16 or CIM-Plates 16

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Located inside a tissue culture incubator, it is capable of switching any one of the wells on the E-Plate 96 to the RTCA Analyzer for impedance measurement

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Located inside a tissue culture incubator, it is capable of switching any one of the wells on any of six E-Plates to the RTCA Analyzer for impedance measurement

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Instrument can be integrated with automated liquid handling platforms or a robotic plate handler from different vendors

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