Cardiac Troponin Activator CK-963 Increases Cardiac Contractility in Rats

Area of Science:

• Cardiovascular Pharmacology
• Biochemistry
• Molecular Cardiology

Background:

• Cardiac contractility is crucial for cardiovascular health.
• Existing inotropes often have side effects, such as increased calcium levels.
• Directly modulating cardiac troponin offers a potential alternative therapeutic strategy.

Purpose of the Study:

• To identify novel activators of cardiac troponin.
• To develop a compound that enhances cardiac contractility without increasing intracellular calcium.
• To evaluate the pharmacological effects of direct cardiac troponin activation.

Main Methods:

• High-throughput screening using a cardiac myofibril ATPase assay.
• Biochemical and biophysical assays for target validation.
• Rat cardiomyocyte and echocardiography studies.
• Isothermal titration calorimetry.

Main Results:

• Identified novel cardiac troponin activators (compounds 1 and 2).
• Compound CK-963 demonstrated potent inotropic effects in rat cardiomyocytes and in vivo, increasing fractional shortening up to 95%.
• CK-963 directly interacts with cardiac troponin (Kd = 11.5 ± 3.2 μM) and lacks phosphodiesterase-3 inhibition.

Conclusions:

• Direct cardiac troponin activation is achievable and pharmacologically tractable.
• CK-963 represents a promising therapeutic candidate for heart failure.
• This approach avoids the detrimental effects of increased intracellular calcium and PDE-3 inhibition.