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Unraveling Kinase Inhibitor Cardiotoxicity with Cardiomyocyte Impedance Assays

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Cardiovascular (CV) toxicity is a leading cause of drug failure. Though implementing earlier testing has successfully reduced hERG-related arrhythmias, additional assays capable of identifying other functional CV effects remain elusive. There is a pressing need to address this gap for kinase inhibitors, which frequently display CV toxicity. In this webinar, Dr. Sarah K. Lamore of AstraZeneca Pharmaceuticals (Waltham, MA) presents her research utilizing cellular impedance measurement of beating cardiomyocytes to deconvolute kinase inhibitor cardiotoxicity. Specific topics covered include: • The principle behind cellular impedance assays • Translational predictivity for cardiac contractility assays (xCELLigence® vs. IonOptix) • CV toxicity assay development for kinase inhibitors (Chk & MARK) that have unresolved functional cardiotoxicity • Progress in Kinome-wide screening & deconvolution using cellular impedance assays Dr. Sarah K. Lamore is a discovery safety scientist at AstraZeneca Pharmaceuticals. Her current research focuses on combining cellular impedance and human iPSC-derived cardiomyocytes to deconvolute kinase inhibitor cardiotoxicity. Dr. Lamore received her Ph.D. in pharmacology and toxicology from the University of Arizona in 2012. Her doctoral work involved identifying cysteine cathepsins as novel targets of UVA-induced photooxidative stress. For more information, please visit: http://www.aceabio.com/product/rtca-cardio/ REFERENCES: 1. Lamore SD, Kamendi HW, Scott CW, Dragan YP, Peters MF. Cellular impedance assays for predictive preclinical drug screening of kinase inhibitor cardiovascular toxicity. Toxicol Sci. 2013 Oct;135(2):402-13. 2. Scott CW, Zhang X, Abi-Gerges N, Lamore SD, Abassi YA, Peters MF. An impedance-based cellular assay using human iPSC-derived cardiomyocytes to quantify modulators of cardiac contractility. Toxicol Sci. 2014 Dec;142(2):331-8. 3. Peters MF, Lamore SD, Guo L, Scott CW, Kolaja KL. Human stem cell-derived cardiomyocytes in cellular impedance assays: bringing cardiotoxicity screening to the front line. Cardiovasc Toxicol. 2015 Apr;15(2):127-39.
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