VIT-2763

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[1].

Signaling Pathways >> Others >> Others

Research Areas >> Metabolic Disease

VIT-2763 dose dependently reduces the fluorescence polarization signal, indicating that VIT-2763 displaces TMR-hepcidin from ferroportin (IC50 of 24 ± 13 nM)[1]. 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[1]. VIT-2763 (100 nM) triggers ubiquitination and subsequent internalization and degradation of ferroportin[1]. Cell Viability Assay[1]. Cell Line: J774 cells. Concentration: 100 nM. Incubation Time: 10, 20, 40, 60, or 120 minutes. Result: Induced ferroportin internalization and ubiquitination.

VIT-2763 (30, 100 mg/kg, orally twice daily for 36 days) decreases serum iron and prevented liver iron loading in Hbbth3/+ mice[1]. VIT-2763 did not change the total liver iron[1]. 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%[1]. VIT-2763 decreases apoptosis and extends the life span of RBCs in Hbbth3/+ mice[1]. Animal Model: Hbbth3/+ mice[1]. Dosage: 30, 100 mg/kg. Administration: Orally twice daily for 36 days. Result: Significantly decreased serum iron levels by 77% (30 mg/kg) and 84% (100 mg/kg), Significantly increased Hb levels (as of day 8 of treatment), RBC counts, mean corpuscular Hb concentration (MCHC), and significantly lowered reticulocyte counts, mean corpuscular Hb (MCH), mean corpuscular volume (MCV), and RBC distribution width (RDW) in Hbbth3/+ mice, as compared with the Hbbth3/+ vehicle group.

[1]. Vania Manolova, et al. Oral Ferroportin Inhibitor Ameliorates Ineffective Erythropoiesis in a Model of β-Thalassemia. J Clin Invest. 2019 Dec 9;130(1):491-506.