Abstract

Cardioprotectants: From Phenotype Screening to Pathway Targets

Siobhan Malany, Director, Translational Biology, Sanford Burnham Prebys Medical Discovery Institute

In the United States alone, approximately one million heart attacks occur per year and only 37% of patients survive one year after suffering a heart attack. A major consequence of myocardial infarction is the loss of cardiomyocytes due to oxidative stress associated with reperfusion. Improving pharmacological therapies that provide protection during cardiac oxidative stress is the focus of significant research and exploratory medicine. We report a chemical biology phenotypic screening approach to identify and validate small molecules that protect human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) from oxidative stress. Cardioprotective activity of ‘hit’ compounds was confirmed using impedance-based detection of cardiomyocyte monolayer integrity and contractile function. Structure-activity relationship studies led to the identification of a potent class of compounds with 4-(pyridine-2-yl)thiazole scaffold. Examination of gene expression in hiPSC-CMs revealed that the hit compound, designated cardioprotectant 312 (CP-312) induces a marker of the antioxidant response network. CP-312 therefore represents a novel chemical scaffold identified by phenotypic high-throughput screening using hiPSC-CMs that activates the antioxidant defense response and may lead to improved pharmacological cardioprotective therapies.