Hemoglobin is the special protein that carries oxygen in red blood cells and gives blood red color. Moreover, globin and heme composes hemoglobin. Thereinto, the globin portion is a tetramer consisting of two distinct pairs of globin chains (alpha and beta).
Interestingly, the beta-globin gene produces HbS (haemoglobin S) when beta-globin has a point mutation. However, HbS polymerizes under hypoxic conditions and leads to the formation of sickled red blood cells (SS RBC) disease. Sickle cell disease is characterized by haemolytic anaemia, vaso-occlusion and a vasculopathy that leads to progressive end-organ damage.
Here, we focus on the HbS polymerization inhibitor, Voxelotor (GBT 440).
Voxelotor is a HbS polymerization inhibitor. Notably, Voxelotor is a potent inhibitor of HbS polymerization. Furthermore, Voxelotor has the potential for sickle cell disease (SCD) treatment.
In vitro, Voxelotor binds to the N-terminal a chain of haemoglobin, increases HbS affinity for oxygen, delays HbS polymerization and prevents sickling of red blood cells (RBCs). Moreover, in a murine model of SCD, Voxelotor extends the half-life of RBCs. And whereafter, Voxelotor reduces reticulocyte counts and prevents ex vivo RBC sickling. Not only that, the PK profile of Voxelotor in various animal species shows a preferential partitioning in the RBC compartment in relation to plasma. Last but not least, oral dosing of Voxelotor in animals demonstrates suitability for once daily dosing in humans and a highly selective partitioning into RBCs.
Taken together, Voxelotor is an HbS polymerization inhibitor. To sum up, Voxelotor is a potent compound of sickle cell disease.
. Oksenberg D, et al. Br J Haematol. 2016 Oct;175(1):141-153.