Afcamten is a small-molecule cardiac myosin inhibitor designed to treat hypertrophic cardiomyopathy (HCM), an inherited disease characterized by excessive cardiac contractility. HCM affects approximately 1 in 500 people and is associated with left ventricular hypertrophy, myofibrillar disarray, fibrosis, and diastolic dysfunction. The first-in-class cardiac myosin inhibitor, mavacamten, has shown promise in improving symptoms in obstructive HCM. Afcamten, a selective inhibitor of cardiac myosin, stabilizes a weak actin-binding state by slowing phosphate release and preventing conformational changes necessary for force generation. Structural analysis reveals that afcamten binds to an allosteric site distinct from mavacamten, targeting the same pocket as the nonselective myosin inhibitor blebbistatin but with higher selectivity for cardiac myosin. In vitro and in vivo studies demonstrate that afcamten reduces cardiac contractility in a dose-dependent manner, both in normal and HCM mouse models. These findings suggest that afcamten holds promise as a therapy for HCM.Afcamten is a small-molecule cardiac myosin inhibitor designed to treat hypertrophic cardiomyopathy (HCM), an inherited disease characterized by excessive cardiac contractility. HCM affects approximately 1 in 500 people and is associated with left ventricular hypertrophy, myofibrillar disarray, fibrosis, and diastolic dysfunction. The first-in-class cardiac myosin inhibitor, mavacamten, has shown promise in improving symptoms in obstructive HCM. Afcamten, a selective inhibitor of cardiac myosin, stabilizes a weak actin-binding state by slowing phosphate release and preventing conformational changes necessary for force generation. Structural analysis reveals that afcamten binds to an allosteric site distinct from mavacamten, targeting the same pocket as the nonselective myosin inhibitor blebbistatin but with higher selectivity for cardiac myosin. In vitro and in vivo studies demonstrate that afcamten reduces cardiac contractility in a dose-dependent manner, both in normal and HCM mouse models. These findings suggest that afcamten holds promise as a therapy for HCM.