Daprodustat (GSK1278863) is an Orally Active HIF-PH Inhibitor

Chronic kidney disease (CKD) is a major global health problem. In general, kidneys can produce erythropoietin (EPO). The level of EPO is negatively correlated with oxygen levels in the blood. Thus forming a negative feedback mechanism for erythropoiesis. So, if the concentrations of plasma EPO do not increase sufficiently when the hemoglobin (Hgb) level is decreased in CDK. It will result in renal anemia.

HIF-prolyl hydroxylase (HIF-PH) is an important oxygen sensor to regulate the expression of HIF. HIF is the main regulatory factor of gene expression during the physiological response to hypoxia. Generally, HIF regulates the transcription and production of multiple downstream targets such as EPO and vascular endothelial growth factor (VEGF) in a manner highly sensitive to oxygen concentration. So, PHI can inhibit HIF-PH, up-regulate EPO levels and increase iron bioavailability, thus improving the iron-restricted erythropoiesis in CKD-associated anemia.

GSK1278863 is a small-molecule oral HIF-PH inhibitor.

Daprodustat (GSK1278863) inhibits the degradation of HIF transcription factors, thereby stabilizing them and activating their downstream effects. On the one hand, PHI can induce endogenous EPO production by manipulating the HIF system, resulting in effective erythropoiesis. On the other hand, GSK1278863 increases EPO levels in anemic CKD patients, leading to increases in hemoglobin, hematocrit and red blood cell numbers. In addition, GSK1278863 also has good safety and tolerability in vivo.

In conclusion, Daprodustat (GSK1278863) is an orally active HIF-PH inhibitor, which can be used for the research of anemia associated with chronic kidney disease.

Reference:

[1]  Brigandi, Richard A et al. American journal of kidney diseases: the official journal of the National Kidney Foundation vol. 67,6 (2016): 861-71.

[2]  Hara, Katsutoshi et al. Drug metabolism and pharmacokinetics vol. 30,6 (2015): 410-8.