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Protein kinase inhibitors (KIs) are used as highly specific cancer targeting agents for their ability to prevent kinase molecules from activating signalling pathways that regulate cellular behaviour, however they have recently been linked to toxicities on the heart that were not detected during clinical trials. We hypothesize that a high-throughput, high-fidelity screening platform for evaluating the physiological effects of KIs on human myocardium could be established using high-content screening assays on hiPSC-derived cardiomyocytes (hiPSC-CM), and engineered heart tissue constructs termed Biowires. 80 KIs were screened using high-content screening assays and artificial neural network modelling, and the least detrimental inhibitor on cardiac function was examined on the Biowire. 3D Biowire tissues were less sensitive to functional improvements and detrimental effects on viability of KIs compared to 2D monolayer cultures. In conclusion, we propose a system linking high throughput screening with empirical modelling to observe the effects of KIs on cardiac tissue.

High-throughput analysis of kinase inhibitor drugs on cardiac function using engineered heart tissue constructs