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.
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PT2385 (PT-2385) is a potent, selective, and orally active antagonist of HIF2α, binds to HIF2α PAS-B domain (Kd=50 nM) and disrupts HIF2α/ARNT dimer formation; allosterically blocks HIF2α dimerization with the HIF1α/2α transcriptional dimerization partner ARNT/HIF1β, disrupts HIF2α, but not HIF1α, heterodimerization with ARNT in Hep3B cells; inhibits the expression of HIF2α-dependent genes, including VEGF-A, PAI-1, and cyclin D1 in ccRCC cell lines and tumor xenografts, also reduces HIF2α mRNA and protein levels in xenograft tumors.
A novel potent HIF-1 inhibitor that inhibits hypoxia-induced upregulation of HIF-1, suppresses tumor cells invasion and angiogenesis; down-regulates VEGF and MMP-2, suppresses angiogenesis induced by hypoxia and VEGF in vitro; inhibits tumor cell migration and invasion by suppressing PI3K/AKT- and MAPK/ERK-dependent HIF-1 pathway.
ML228 (ML-228, CID-46742353) is an activator of the hypoxia inducible factor (HIF) pathway with EC50 of 1.4 uM in HIF-1α nuclear translocation assays; demonstrates to potently activate HIF in vitro as well as its downstream target VEGF (EC50=1.63 uM); significantly augmentes VEGFR-2, attenuates Caspase-3 and neuronal apoptosis, and improves neurological Severity Score and tissue edema in the hippocampus of rats, without affecting expression of NF-κB.
IDF-11774 (IDF 11774, IDF11774) is a potent, orally bioavailable HIF-1 inhibitor that reduces the HRE-luciferase activity of HIF-1α (IC50=3.65 uM) and blocks HIF-1α accumulation under hypoxia in HCT116 human colon cancer cells; suppresses the mRNA expression of HIF-1 target genes VEGF and EPO but not HIF-1α; inhibits the accumulation of HIF-1α in vitro and in vivo in colorectal carcinoma HCT116 cells; exhibits substantial anticancer efficacy in mouse models containing KRAS, PTEN, or VHL mutations.
Enarodustat is a novel potent, orally active HIF prolyl hydroxylase (PHD) inhibitor with IC50 of 0.22 uM for PHD2; increases EPO release from Hep3B cells with EC50 of 5.7 uM, increases hemoglobin levels in rats.
Arylsulfonamide 64B (HIF inhibitor 64B) is a small molecule HIF pathway inhibitor, blocks hypoxia-induced expression of c-Met and CXCR4 and uveal melanoma (UM) cell migration; blocks HIF-1α association with co-factors p300 and CBP at low micromolar concentrations, disrupts the HIF transcription complex by interfering with HIF-1α recruitment of p300/CBP co-factors on hypoxia-responsive elements on target genes; demonstrates strong anti-cancer activity in syngeneic and xenogeneic orthotopic UM mouse models, Arylsulfonamide 64B (64B) is a potent inhibitor of the hypoxiainduced CXCR4 and c-Met-mediated signaling axis that controls in vitro tumor cell motility; shows potent anti-tumor activity at the primary melanoma growth site in the eye, reduces circulating tumor cells, and strongly inhibits spontaneous formation and expansion of metastases in the liver with minimal toxicity.
KCN1 (HIF inhibitor KCN1) is a small molecule inhibitor of the HIF-1 pathway, antagonizes HIF transcription in bioassay, blocks the p300/HIF-1α interaction, and exert potent anticancer activity in vitro and in vivo; specifically inhibits HIF reporter gene activity in several glioma cell lines at the nanomolar leve, also downregulates transcription of endogenous HIF-1 target genes, such as VEGF, Glut-1, and carbonic anhydrase 9, in a hypoxia-responsive element (HRE)-dependent manner; inhibits in vivo glioma growth and interferes with HIF signaling by disrupting HIF-1α interaction with cofactors p300/CBP.
JNJ-42041935 is a potent, selective, 2-OG-competitive, reversible inhibitor of HIF-PHD with pKi of 7.91, 7.29 and 7.65 for PHD1, PHD2 and PHD3, respectively; shows highly selectivity for PHD relative to FIH (pIC50=4.0); JNJ-42041935 is approximately equipotent in the HIF-1α accumulation and erythropoietin secretion assays in Hep3B cells as DMOG and 3,4-EDHB; reverses inflammation-induced anemia at dose of 100 μmol/kg, whereas erythropoietin has no effect.
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.
KHS-101 (KHS101) is a small molecule that selectively induces a neuronal differentiation phenotype, induces neuronal differentiation in cultured hippocampal neural progenitor cells (NPCs) by interacting with TACC3 (EC50=1 uM); works indirectly on HIF complex formation by destabilizing both TACC3 and the HIF component HIF-1α, decreases TACC3 levels in cells and regulates HIF gene expression; significantly increases neuronal differentiation in rats in vivo.
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