Prokineticins are angiogenic hormones that activate two GPCR: PKR1 and PKR2. Through a combination of in silico studies, hit to lead optimization, and pharmacological profiling approaches, we designed, synthesized, and characterized the first PKR1 agonists, demonstrating their cardioprotective activity against myocardial infarction in mice. The most potent derivative, IS20, was confirmed for its selectivity and specificity through genetic gain- and loss-of-function of PKR1. Importantly, IS20 prevented cardiac lesion formation and improved cardiac function after myocardial infarction in mice, promoting proliferation of cardiac progenitor cells and neovasculogenesis. The preclinical investigation of the first PKR1 agonists provides a novel approach to promote cardiomyocyte survival and vascular stabilization after myocardial infarction. Recently we demonstrated that IS20 alleviates doxorubicin (DOX)-cardiotoxicity in cardiac cells and in mice models of acute and chronic DOX-cardiotoxicity. More importantly, IS20 did not alter the cytotoxic and anti-tumor effects of DOX in breast cancer lines or in mouse breast cancer models. Our study provides therapeutic strategies to combat cardiotoxicity in cancer and cardiomyopathy after myocardial infarction.