FG-2216

FG-2216 (YM-311, IOX3) is a selective small molecule inhibitor of HIF prolyl hydroxylase with IC50 of 3.9 nM (PDH2), decreases protein expression of DNA/RNA demethylase FTO (in C2C12 cells) and reduces maximal respiration rate in vitro; up-regulates HIF-1α and increases erythropoietin expression in mice, also significantly reduces bone mineral density and content and alter adipose tissue distribution in mice; FG-2216 is orally bioavailable and induced significant and reversible Epo induction in vivo. (In Vitro) :FG-2216 (50-100 μM; 24 h) stimulates erythropoietin (Epo) secretion by PHD2 inhibition in Hep3B cells.FG-2216 (3-100 μM; 24 h) stabilizes HIF-1α and HIF-2α in Hep3B cells. (In Vivo) :FG-2216 (40-60 mg/kg; p.o. twice a week for 150 d) induces erythropoiesis and a small elevation of hemoglobin (HbF) expression, and is well tolerated in rhesus macaques.FG-2216 (50 mg/kg; p.o. once daily for 4 or 12 d) increases hematocrit, red blood cell counts, and hemoglobin levels in mice.FG-2216 (40-60 mg/kg; a single p.o) reversibly induces endogenous Epo in rhesus macaques.