THE NOVEL ORAL SMALL MOLECULE CPD-348 CLOSELY MIMICS HEPCIDIN AND AMELIORATES ERYTHROCYTOSIS IN MICE

The 25 amino acid peptide hormone hepcidin regulates the systemic iron pool by inducing internalization and degradation of the cellular iron exporter ferroportin. Hepcidin replacement therapy could be applied to a variety of diseases including polycythemia vera (PV), hereditary hemochromatosis, β-thalassemia, and myelodysplastic syndrome. While multiple hepcidin mimetics have been developed, no orally bioavailable small molecule has been described that closely mimics hepcidin-mediated ferroportin internalization. In this present study we report the first oral small molecule hepcidin mimetic, Compound 348 (Cpd-348), that induces ferroportin internalization comparable to hepcidin, and ameliorates erythrocytosis in a mouse model of PV.

Cpd-348 resulted in loss of luciferase activity in an inducible luciferase-tagged ferroportin internalization assay in CHO cells (IC50=10 nM). Furthermore, on T47D cells that endogenously express ferroportin, Cpd-348 diminished ferroportin surface expression with similar efficacy when compared to hepcidin whereas the previously published hepcidin mimetic vamifeport does not. Using a fluorescence polarization assay with recombinant ferroportin and labeled hepcidin, we observed that Cpd-348 directly inhibits the ferroportin–hepcidin interaction. Next, we tested the effect of Cpd-348 in vivo. In naïve mice, Cpd-348 mixed into the animal diet (0.03%, 0.1%, and 0.3%) caused dose-dependent microcytosis and reduction in reticulocyte hemoglobin. More interestingly, in a disease model of PV, Cpd-348 lowered serum iron concentrations and ameliorated the erythrocytosis.

In summary, we report that Cpd-348 is the first oral small molecule hepcidin mimetic that closely mimics hepcidin function and ameliorates PV. Cpd-348 may be a therapeutic option for the treatment of PV and other hepcidin-related disorders.