FG-2216 is a potent HIF-prolylhydroxylase inhibitor with IC50 of 3.9 μM for PHD2 enzyme, orally bioavailable and induced significant and reversible Epo induction in vivo.
The family of HIF-PH (HIF prolyl hydroxylase) enzymes are the main molecular to regulate HIF activity through hydroxylation at 2 proline residues and cause the degradation of HIF, thus leading to inhibition on accumulation of functional HIF under normoxia. FG-2216 is the PHD inhibitor with IC50 value of 3.9μM for PHD2 (measure by SAR study). Treatment with FG-2216 for 24h can stabilize HIF-1α and HIF-2α in Hep3B cells. Significant increase of EPO, as well as obvious band of HIF-1α and HIF-2α can be observed in Hep3B cells treated with 100μM FG-2216 for 24h[1]. Pre-treatment with FG-2216 at dose of 25 or 50mg/kg, b.w., i.p., 6h prior to initiation of ischaemia, caused HIF-1α and HIF-2α accumulation in kidney of rats, accompanied with increased transcriptional level of HIF targeted gene EPO and Glut-1[2]. FG-2216 increased hemoglobin in healthy volunteers and hemodialysis patients with CKD in a phase IIa study. Thus, it was regarded as the lead drug candidate for the treatment of CKD-related anaemia[3].
作用机制
FG-2216 can bind with the catalytically active domain of human PHD2 and fill the empty spaces with hydrophobic functional groups.[1]
FG 2216 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
HEK293 cells
Function assay
Inhibition of WNT3A signaling in HEK293 cells by luciferase reporter gene assay in presence of forskolin, IC50=3.5 nM
23844574
Hep3B cells
Function assay
Inhibition of PHD2 in human Hep3B cells assessed as erythropoietin secretion by ELISA, IC50=3.9 μM
24894560
Hep3B cells
100 uM
Function assay
24 h
Inhibition of PHD2 in human Hep3B cells assessed as increase in erythropoietin secretion at 100 uM after 24 hrs by ELISA
搜索
