Cardiac Selective Modulator of Human Myosin for the Treatment of Genetic Hypertrophic Cardiomyopathy

Genetic hypertrophic cardiomyopathy (HCM) results from mutations in the cardiac sarcomere, including β-cardiac myosin, with HCM afflicting about 1 out of every 500 people in the United States. HCM is characterized by hyper-contractility and myocyte hypertrophy. Current agents used to treat HCM include β-blockers and Ca2+ channel blockers to decrease the hyper-contractility and improve cardiac relaxation. A novel and more direct approach to decreasing hyper-contractility and improving diastolic relaxation in HCM patients is by modulating β-cardiac myosin to produce less force. We believe modulation at the sarcomere level provides a focused strategy while lowering the potential for adverse drug events. In this study we examined the effects of MYK0000461, a cardiac myosin selective inhibitor, on adult rat cardiomyocytes to fully understand the mechanism of action on excitation-contraction (E-C) coupling. Cellular contractility was assessed using edge detection and the calcium transient was measured using fura-2 loaded myocytes. MYK0000461 decreased contractility in a dose dependent manner with an IC50 of 250nM without altering the calcium transient. This inhibitory effect can be reversed by stimulation of the β-adrenergic pathway with the known agonist isoproterenol. We hypothesize that modulation of mutant β-cardiac myosin activity with a small molecule agent such as MYK0000461 could potentially treat disorders resulting from hyper-contractility such as HCM.