Ischemic heart disease, the largest cause of morbidity and death globally, is a significant therapeutic target. There was no effective treatment for decreasing cardiac I/R damage. CaMKII (Ca2+/calmodulin-dependent kinase II) is important in the pathophysiology of severe cardiac diseases such as I/R damage. Pharmacological CaMKII inhibition is an essential technique in preventing myocardial damage and heart disorders. There was no medication targeting CaMKII for therapeutic treatment of cardiac disease. Furthermore, there was no specific inhibitor of CaMKII-δ the predominant CaMKII isoform in the heart.
To screen for CaMKII-δ9 inhibitors, a small-molecule kinase inhibitor library and a high-throughput screening technology for the kinase activity test of CaMKII-δ9 (the most prevalent CaMKII-δ splice variant in the human heart) were utilized. For a study, researchers sought to investigate the protection of hesperadin against cardiomyocyte death and cardiac diseases using cultured neonatal rat ventricular myocytes, human embryonic stem cell-derived cardiomyocytes, and in vivo mouse models, in conjunction with myocardial injury induced by I/R (or hypoxia/reoxygenation) and CaMKII-δ9 overexpression. In addition, the in vivo anticancer activity of hesperadin was evaluated using BALB/c nude mice with xenografted tumors of human cancer cells.
They discovered that hesperadin, an Aurora B kinase inhibitor with anticancer action in vitro, directly bound to CaMKII-δ and precisely prevented its activation in an ATP-competitive manner using the small-molecule kinase inhibitor library and screening technique. Moreover, in both rats and human embryonic stem cell-derived cardiomyocytes, hesperadin effectively alleviated I/R- and overexpressed CaMKII-δ9 induced cardiomyocyte mortality, myocardial injury, and heart failure.
They discovered hesperadin to be a selective small-molecule inhibitor of CaMKII-δ with cardioprotective and anticancer properties. The findings not only implied that hesperadin is a promising leading chemical for clinical therapy of cardiac I/R damage and heart failure but also provided a method for the combined treatment of cancer and cardiovascular illness induced by anticancer treatment.
Reference:www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.055920
