HIFs (Hypoxia-inducible factors) are transcription factors that respond to changes in available oxygen in the cellular environment, to be specific, to decreases in oxygen, or hypoxia. The HIF signaling cascade mediates the effects of hypoxia, the state of low oxygen concentration, on the cell. Hypoxia often keeps cells from differentiating. However, hypoxia promotes the formation of blood vessels, and is important for the formation of a vascular system in embryos, and cancer tumors. The hypoxia in wounds also promotes the migration of keratinocytes and the restoration of the epithelium. In general, HIFs are vital to development. In mammals, deletion of the HIF-1 genes results in perinatal death. HIF-1 has been shown to be vital to chondrocyte survival, allowing the cells to adapt to low-oxygen conditions within the growth plates of bones. HIF plays a central role in the regulation of human metabolism. Recently, several drugs that act as selective HIF prolyl-hydroxylase inhibitors have been developed.
PX-478 is an inhibitor of hypoxia-inducible factor-1α (HIF-1α), and is cytotoxic to a variety of cancer cell lines under normoxia and hypoxia in vitro with IC50 of 20-30 μM.
2-Methoxyestradiol is a microtubule and HIF-1 inhibitor, binds to tubulin at or near the colchicine site and inhibits the polymerization of tubulin in vitro, works by interfering with normal microtubule function.
IDF-11774 is a novel hypoxia-inducible factor (HIF)-1 inhibitor with an IC50 of 3.65 μM. IDF-11774 has been approved as a clinical candidate for a phase I study.
Daprodustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor being developed for treatment of anemia associated with chronic kidney disease.
Molidustat (BAY 85-3934) is a novel inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH) with mean IC50 values of 480 nM for PHD1, 280 nM for PHD2, and 450 nM for PHD3.
Oltipraz has an inhibitory effect on HIF-1α activation by insulin in a time-dependent manner, completely abrogating HIF-1α induction at ≥10 μM concentrations, the IC50 of Oltipraz for HIF-1α inhibition is 10 μM.
Chlorogenic acid(NSC-407296; 3-O-Caffeoylquinic acid) is one of the most abundant polyphenols in the human diet, has been reported to inhibit cancer cell growth and a major anti-inflammatory constituent of lonicerae flos extract.
FG-2216 is a potent HIF-prolyl hydroxylase inhibitor with IC50 of 3.9 uM for PDH2 enzyme; orally bioavailable and induced significant and reversible Epo induction in vivo.
JNJ-42041935 is a potent, competitive and selective inhibitor of prolyl hydroxylase PHD; inhibits PHD1, PHD2, and PHD3 with pKi values of 7.91±0.04, 7.29 ±0.05, and 7.65±0.09, respectively.
