At last week’s 57th Annual Meeting and ToxExpo (in San Antonio, Texas), the Society of Toxicology announced “Deconvoluting Kinase Inhibitor Induced Cardiotoxicity” as its paper of the year for 2017.
At last week’s 57th Annual Meeting and ToxExpo (in San Antonio, Texas), the Society of Toxicology announced “Deconvoluting Kinase Inhibitor Induced Cardiotoxicity” as its paper of the year for 2017. Under the leadership of Sarah Lamore and Matthew Peters, this seminal publication used xCELLigence Real-Time Cell Analysis to quantify the impact of 65 small molecule kinase inhibitors (KIs) on the beating activity of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM). Enabling a rigorous assessment of cardiomyocyte function, rather than a limited biochemical readout, the xCELLigence assay elucidated drug-induced changes in both beating rate and amplitude. Computational analyses were then employed to establish correlations between these observed beating effects and previously published in vitro kinase inhibition profiles for each drug. Using this approach along with siRNA-mediated knockdown of individual kinases expressed in hiPSC-CM, the authors were able to identify which kinases, out of the hundreds that are encoded in the human genome, are involved in excitation-contraction coupling in cardiomyocytes.
Because kinases play crucial roles in regulating diverse cellular processes, they are prime targets for pharmacological intervention in diseases such as cancer. However, because the 518 human kinases have high structural similarity within their active sites, small molecule KIs typically display promiscuity, binding to and inhibiting more than one kinase. A notorious consequence of this poor specificity is cardiotoxicity, and many KI drugs “have their clinical utility limited by cardiotoxicity-related label warnings or prescribing restrictions,” explained the authors. A major challenge in overcoming this cardiotoxicity problem is being able to identify, for each KI drug, precisely which kinase is responsible for the toxic phenotype in vivo. By coupling the functional cardiomyocyte assay of the xCELLigence instrument with a burgeoning database of publicly available in vitro kinase inhibitor data, the authors were able to cope with the promiscuity issue and identify the subset of kinases which are responsible for cardiotoxicity. Importantly, the authors identified three sentinel kinases for which the absence of drug-induced inhibition is predictive of clinical safety.
Stating that xCELLigence “impedance-based assays with hiPSC-CM have proven highly predictive for each of the leading functional cardiotoxicity hazards”, the authors concluded that pharmacology now has “the opportunity for a paradigm shift from the present era where the majority of small molecule KI drugs exhibit cardiotoxicity in the clinic, to rational design of small molecule KI cardiovascular safety.”
View the complete publication here.
About xCELLigence RTCA and the CardioECR Instrument
ACEA’s xCELLigence® Real Time Cell Analysis (RTCA) instruments utilize gold microelectrodes embedded in the bottom of microtiter wells to non-invasively monitor the status of adherent cells using the principle of cellular impedance. In short, cells act as insulators – impeding the flow of an alternating microampere electric current between electrodes. This impedance signal is measured automatically, at an interval defined by the user, and provides an extremely sensitive readout of cell number, cell size/shape, and cell-substrate attachment strength. Unique amongst the xCELLigence line of instruments, the CardioECR model combines real-time impedance recording with field potential measurement and a pacing function to provide a view of cardiomyocyte health at an unprecedented level of detail. Learn more about the xCELLigence Cardio ECR instrument and how it is revolutionizing cellular cardiology research.
About ACEA Biosciences
Founded in 2002, ACEA Biosciences is a pioneer in the development and commercialization of high performance, cutting edge cell analysis platforms for life science research. ACEA’s xCELLigence® impedance-based, label-free, real-time cell analysis instruments and NovoCyte® flow cytometer are used in pre-clinical drug discovery and development, toxicology, safety pharmacology, and basic academic research. More than 2,000 instruments have been placed globally, leading to >1,250 peer reviewed publications.
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Dr. Jeff Xue
