Hypercontractility of the cardiac sarcomere may be essential for the underlying pathological hypertrophy and fibrosis in genetic hypertrophic cardiomyopathies. CK-274 is a novel cardiac myosin inhibitor that directly decreases cardiac muscle contractility and may be a treatment for hypercontractility of the cardiac sarcomere in hypertrophic cardiomyopathies. CK-274 attenuates cardiac muscle function by slowing the rate-limiting, actin-activated phosphate release without affecting ATP binding or hydrolysis. The optimization of CK-274 focused not only on selective target engagement, but also on safety and DMPK properties. The key optimization parameters included: 1) a projected human t1/2 to enable QD dosing and reaching steady state plasma concentrations within 2 weeks, 2) rapid cessation of effect after dosing is completed, 3) a shallow concentration-effect relationship in vivo, and 4) avoidance of potential drug-drug interactions (DDI). In conclusion, CK-3773274 is a novel, small molecule, cardiac myosin inhibitor that reduces cardiac contractility in vitro and in vivo. Cardiac myosin inhibition may be a viable approach to treat the underlying hypercontractility of the cardiac sarcomere in hypertrophic cardiomyopathies. CK-274 is currently being evaluated in phase 2 in a multi-center, randomized, double-blind, placebo-controlled, dose-finding study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of it in adults with symptomatic hypertrophic cardiomyopathy and left ventricular outflow tract obstruction.

Discovery of CK-274: A novel, small molecule, cardiac myosin inhibitor for the treatment of hypertrophic cardiomyopathies (HCM)

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.