pyruvate kinase-R activator AG-946

An orally available activator of the red cell isoform of pyruvate kinase (PK-R; PKR), with potential to improve hemolytic anemia and related-symptoms in patients with pyruvate kinase deficiency (PKD). Upon oral administration, PKR activator AG-946 binds to and activates PKR, thereby enhancing glycolytic pathway activity in red blood cells (RBCs), improving adenosine triphosphate (ATP) levels and reducing 2,3-diphosphoglycerate (2,3-DPG) levels. This may result in increased oxygen affinity, improved RBC deformability, decreased sickle RBC hemolysis, increased hemoglobin (Hb) levels and improved RBC membrane function. Mutations in PKR cause deficiency in PKR which prevents adequate RBC glycolysis, leading to a build-up of the upstream glycolytic intermediate 2,3-DPG and deficiency in the PKR product ATP.