AG-946 (Tebapivat, AG946) is a potent, allosteric activator of wild-type and mutant RBC-specific form of pyruvate kinase (PKR) with AC50 of 5 nM for human wild-type PK, 4.3 nM and 6.9 nM for mutated K410E and R510Q PK proteins, resepctively.
AG-946 activates both WT PKR and a panel of prototypically unstable PKR mutants.
AG-946 stabilizes PKR R510Q, an unstable mutant PKR enzyme, and preserves its catalytic activity under increasingly denaturing conditions.
AG-946 demonstrated good activity in cell-based assays using purified RBCs, with an average AC50 for PKR activation of 35 nM and an average maximum percent PKR activation of 197%.
AG-946 represents a new investigational PK activator with potential for low projected human drug load and long pharmacodynamic duration of action, suitable for clinical development in a broad range of hemolytic anemias and diseases characterized by dyserythropoiesis.