AG-946: Enhancing Pyruvate Kinase Activity and Reducing Sickle Cell Crisis

Sickle cell disease (SCD) is a genetic disorder characterized by anemia and crises due to the stiffening and sickling of red blood cells (RBCs), caused by abnormal hemoglobin S. This sickling is influenced by glycolytic compounds such as 2,3-diphosphoglycerate (2,3-DPG) and ATP. A study previously highlighted that pyruvate kinase (PKR), a glycolysis enzyme, is impaired in SCD and that treatment with mitapivat, an activator of PKR, can reduce sickling. Mitapivat is currently in clinical trials for SCD.

A new study explores the effects of AG-946, a novel PKR activator, on RBCs from SCD patients compared to mitapivat. Blood samples from SCD patients were treated with different concentrations of mitapivat and AG-946, and the activity of PKR and its thermostability were measured. The levels of ATP and 2,3-DPG were also assessed, along with hemoglobin oxygen affinity (p50) and RBC sickling tendency.

The results showed that AG-946, like mitapivat, increased PKR activity and its thermostability. Both treatments decreased 2,3-DPG levels and improved the ATP/2,3-DPG ratio, leading to a significant reduction in p50. This was associated with a reduction in the Point-of-Sickling (PoS), indicating a lower tendency for RBCs to sickle. AG-946 demonstrated these benefits at lower concentrations than mitapivat.

In conclusion, AG-946 activates and stabilizes PKR, reduces 2,3-DPG, improves the ATP/2,3-DPG ratio and p50, and lowers the PoS in SCD RBCs. This suggests that AG-946 could be a potent PKR activator for SCD, offering a promising therapeutic alternative to mitapivat for the treatment of SCD and other anemias.