Cell lines

Adult rat ventricular cardiomyocytes

Preparation method

The solubility of this compound in DMSO is >13.7mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

IC50: 0.18 mM

Applications

MYK-461 inhibited myosin ATPase and contractility of cardiomyocytes. Treatment of mouse cardiac myofibrils with MYK-461 dose-dependently reduced ATPase activity.

Animal models

Wild-type (WT) and HCM mice expressing a–cardiac myosin heavy chain missense mutations R403Q, R719W, or R453C.

Dosage form

2.5 mg/kg per day via drinking water.

Application

MYK-461 reduced the development of myocardial disarray and fibrosis in mouse models of HCM. In adult rat ventricular cardiomyocytes, MYK-461 dose-dependently reduced the fractional shortening without changing the calcium transient. HCM mice treated with MYK-461 had left ventricular wall thickness (LVWT) comparable to that of WT mice.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

MYK-461 is a small molecular chemical that reduces contractility by decreasing the adenosine triphosphatase activity of the cardiac myosin heavy chain.

MYK-461 reduced ATPase activity in a dose-dependent manner with IC50 value of 0.3 mM after treatment of mouse cardiac myofibrils. MYK-461 (>10 mM) decreased the maximal ATPase rate by ~90%. MYK-461 is active against both the A and B isoforms of cardiac myosin.

Treatment with MYK-461 decreased the rate of phosphate release in a dose-dependent manner without slowing adenosine diphosphate (ADP) release. MYK-461 decreases the myosin duty ratio and thus reduces the ensemble power, force and contractility produced by the sarcomere. Exposure to MYK-461 reduced maximal tension in a dose-dependent manner (~70% reduction at 1.0 mM) without altering the pCa50 or the tension at lower calcium concentrations.

MYK-461 showed a dose-dependent reduction in fractional shortening (IC50=0.18 mM) without changing the calcium transient after treated with adult rat ventricular cardiomyocytes. MYK-461 plasma exposures decreased fractional shortening in WT and mutant mice. Although MYK-461 inhibits the ATPase activity of skeletal myosin with a lower affinity (IC50 of 4.7 mM with rabbit skeletal myosin), treated rodents had no reduction in grip strength or voluntary exercise capacity. MYK-461 reduced cardiac contractility in a dose-dependent manner in normal and mutant mice without overt impairment of skeletal muscle function. MYK-461 was administered after the development of substantial hypertrophy, it did not significantly reduce the occurrence of fibrosis. Prehypertrophic R403Q mice treated with MYK-461 had 30% more aligned cardiomyocytes (59 ± 10%; P = 0.02).

Reference:

[1].A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice. Science, 2016. Vol 351,6273.