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Updated: Feb 22, 2026
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Kinase inhibitor screening using artificial neural networks and engineered cardiac biowires
Genevieve Conant1,2, Samad Ahadian2, Yimu Zhao1
1Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada.
Abstract:
Kinase inhibitors are often used as cancer targeting agents for their ability to prevent the activation of cell growth and proliferation signals. Cardiotoxic effects have been identified for some marketed kinase inhibitors that were not detected during clinical trials. We hypothesize that more predictive cardiac functional assessments of kinase inhibitors on human myocardium can be established by combining a high-throughput two-dimensional (2D) screening assay and a high-content three-dimensional (3D) engineered cardiac tissue (BiowireTM) based assay, and using human induced pluripotent stem cell-derived CMs (hiPSC-CMs). A subset (80) of compounds from the GlaxoSmithKline published kinase inhibitor set were tested on hiPSC-CM monolayers and significant effects on cell viability, calcium transients, and contraction frequency were observed. Artificial neural network modelling was then used to analyze the experimental results in an efficient and unbiased manner to select for kinase inhibitors with minimal effects on cell viability and function. Inhibitors of specific interest based on the modeling were evaluated in the 3D Biowire tissues. The three-dimensional Biowire platform eliminated oversensitivity in detecting both Ca2+ transient amplitude enhancements as well as the acute detrimental effects on cell viability due to the kinase inhibitor application as compared to the monolayer testing.
Insights
This study introduces a novel cardiac safety assessment for kinase inhibitors using engineered heart tissue. Combining 2D and 3D assays with artificial neural networks improves prediction of cardiotoxicity in cancer drugs.
Area of Science:
- Cardiovascular toxicology
- Drug discovery and development
- Stem cell biology
Background:
- Kinase inhibitors are vital cancer therapeutics, but some exhibit cardiotoxicity not identified in clinical trials.
- Predictive models for cardiotoxicity are crucial for safe drug development.
Purpose of the Study:
- To develop a more predictive cardiac functional assessment for kinase inhibitors.
- To combine high-throughput 2D and 3D engineered cardiac tissue assays using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).
Main Methods:
- Screening of 80 kinase inhibitors on hiPSC-CM monolayers to assess viability, calcium transients, and contraction.
- Utilizing artificial neural network (ANN) modeling for unbiased analysis and inhibitor selection.
- Evaluating selected inhibitors on a 3D Biowire platform for advanced cardiac tissue assessment.
Main Results:
- Significant effects on hiPSC-CM viability, calcium transients, and contraction frequency were observed in 2D assays.
- ANN modeling efficiently identified kinase inhibitors with minimal impact on cell viability and function.
- The 3D Biowire platform demonstrated reduced oversensitivity compared to monolayer testing, providing a more refined assessment of cardiac effects.
Conclusions:
- A combined 2D and 3D assay approach using hiPSC-CMs offers enhanced predictive power for kinase inhibitor cardiotoxicity.
- ANN modeling aids in unbiased selection of safer kinase inhibitors.
- The 3D Biowire system provides a more physiologically relevant platform for evaluating drug-induced cardiac effects.
