VIT-2763, an oral ferroportin inhibitor, inhibits hepcidin binding to ferroportin and blocks iron efflux. VIT-2763 has the potential in the treatment of β-thalassemia.In Vitro: VIT-2763 dose dependently reduces the fluorescence polarization signal, indicating that VIT-2763 displaces TMR-hepcidin from ferroportin (IC50 of 24 ± 13 nM).
VIT-2763 induces BLA reporter gene activity with an average EC50 of 140 ± 50 nM, as a consequence of increasing intracellular iron concentrations caused by blocked iron export in HEK293 cells.
VIT-2763 (100 nM) triggers ubiquitination and subsequent internalization and degradation of ferroportin.
In Vivo: VIT-2763 (30, 100 mg/kg, orally twice daily for 36 days) decreases serum iron and prevented liver iron loading in Hbbth3/+ mice.
VIT-2763 did not change the total liver iron.
VIT-2763 (30, 100 mg/kg, orally twice daily for 36 days) significantly corrects anemia and improved RBC parameters in Hbbth3/+ mice. VIT-2763 decreases the percentage of ROS-positive RBCs in Hbbth3/+ mice from 67% to 30%.
VIT-2763 decreases apoptosis and extends the life span of RBCs in Hbbth3/+ mice.