Aficamten is a small-molecule cardiac myosin inhibitor designed to treat hypertrophic cardiomyopathy (HCM). It works by inhibiting the ATPase activity of cardiac myosin, slowing phosphate release, and stabilizing a weak actin-binding state. Unlike mavacamten, aficamten binds to a distinct allosteric site on the myosin catalytic domain, preventing conformational changes necessary for strong actin binding and force generation. This reduces the number of functional myosin heads driving sarcomere shortening. The crystal structure of aficamten bound to cardiac myosin in the pre-powerstroke state reveals its binding site and explains its selectivity over smooth and fast skeletal muscle myosin. Aficamten reduces cardiac contractility in cardiac myocytes and in mice with the R403Q cardiac myosin mutation. It is well-tolerated in clinical trials and shows promise as a therapy for HCM. Aficamten has a distinct mechanism of action, with a high potency and selectivity for cardiac myosin, and it reduces cardiac contractility in vitro and in vivo. It is a promising treatment for HCM, with potential for broader application in diseases involving cardiac hypercontractility.Aficamten is a small-molecule cardiac myosin inhibitor designed to treat hypertrophic cardiomyopathy (HCM). It works by inhibiting the ATPase activity of cardiac myosin, slowing phosphate release, and stabilizing a weak actin-binding state. Unlike mavacamten, aficamten binds to a distinct allosteric site on the myosin catalytic domain, preventing conformational changes necessary for strong actin binding and force generation. This reduces the number of functional myosin heads driving sarcomere shortening. The crystal structure of aficamten bound to cardiac myosin in the pre-powerstroke state reveals its binding site and explains its selectivity over smooth and fast skeletal muscle myosin. Aficamten reduces cardiac contractility in cardiac myocytes and in mice with the R403Q cardiac myosin mutation. It is well-tolerated in clinical trials and shows promise as a therapy for HCM. Aficamten has a distinct mechanism of action, with a high potency and selectivity for cardiac myosin, and it reduces cardiac contractility in vitro and in vivo. It is a promising treatment for HCM, with potential for broader application in diseases involving cardiac hypercontractility.