Assessing the capacity of available pharmaceuticals to protect human PSC-derived cardiomyocytes from anthracycline cardiotoxicity

Human induced pluripotent stem cell (hPSC)-derived cardiomyocytes provide a human model to discover compounds that protect the heart during anthracycline chemotherapy. We used hPSC-derived cardiac monolayers to screen an Open Drugs library of 2,906 compounds to identify molecules that prevent doxorubicin-induced cardiomyocyte death. An orthogonal screen of 129 compounds identified as cardioprotective was performed in MCF7 breast cancer cells and MCF10A breast epithelial cells to ensure candidates did not interfere with doxorubicin’s anti-neoplastic activity or exert overt toxicity to non-cancerous, proliferative cells. Two compounds with cardioprotective effects (Cilnidipine and 3,3’-Diindolymethane) were selected – based on efficacy, chemical properties, and mechanism – for structure-activity relationship analyses to improve cardioprotection. Although some analogues showed increased potency in monolayers, validation in 3D hPSC-derived cardiac organoids revealed compromised contractility at cardioprotective doses. Here, we provide the drug screen dataset in raw and processed forms.