HIF

Deferoxamine(Desferrioxamine B) is an iron chelator (binds Fe(III) and many other metal cations) that inhibits neuronopathy, may be used to modify the reduction of iron accumulation and deposition in tissues, and may improve neurological dysfunction by inhibiting ferroptosis and neuroinflammation following traumatic brain injury.Desferrioxamin-B has antioxidant, antiproliferative, Deferoxamine has antioxidant, antiproliferative, and antitumor activities, and can induce HIF-1α production, apoptosis and autophagy in cancer cells.Desferrioxamin-B can be used in the treatment of acute iron toxicity and COVID-19 related diseases.

PX-478 is a HIF-1α inhibitor with selectivity, oral activity, and blood-brain barrier permeability. PX-478 has antitumor activity and also protects pancreatic β-cell function in diabetes mellitus and is used in type 2 diabetes mellitus research.

PT2399 shows effective antitumor activity in vivo. PT2399 is an effective and selective HIF-2α antagonist, which directly binds to the HIF-2α PAS B domain (IC50: 6 nM).

Belzutifan (MK-6482) is a potential treatment for clear cell renal cell carcinoma (ccRCC). Belzutifan is an orally active and selective HIF-2α inhibitor (IC50: 9 nM). Belzutifan , as a second-generation HIF-2α inhibitor, increases potency and improves pharmacokinetic profile.

Dapagliflozin (BMS-512148) is a selective sodium-glucose co-transporter subtype 2 (SGLT2) inhibitor with antihyperglycemic activity.

Oligomycin is an antifungal antibiotic that is an inhibitor of H+-ATP synthetase. The Oligomycin blocks oxidative phosphorylation and the electron transport chain. Oligomycin inhibited HIF-1alpha expression in hypoxic tumor cells.

Roxadustat (FG-4592) is an orally bioavailable, hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), with potential anti-anemic activity.

Cucurbitacin B (Cuc B) has profound in vitro and in vivo antiproliferative effects against human pancreatic Y cells. It inhibited AKT signaling activation through up-regulation of PTEN. Cucurbitacin B is an effective inhibitor of HIF-1 and provide new perspectives into the mechanism of its anticancer activity. Cucurbitacin B inhibits proliferation and induces apoptosis via STAT3 pathway inhibition in A549 lung Y cells.

DMOG (Dimethyloxalylglycine), an antagonist of the α-ketoglutarate cofactor, is an inhibitor for HIF prolyl hydroxylase.

PT-2385 is a selective inhibitor of HIF-2α with a dissociation constant (Kd) of less than 50 nM (Kd<50 nM).

LW6 (HIF-1α inhibitor) is a novel HIF-1 inhibitor.

TC-S 7009 is a potent and selective HIF-2α inhibitor (Kd: 81 nM) with significantly higher affinity for HIF-2α than HIF-1α (Kd >> 5μM). TC-S 7009 disrupts HIF-2α heterodimerization, reduces HIF-2α target gene expression, and diminishes DNA binding activity.

Ganetespib (STA-9090) is a synthetic small-molecule inhibitor of heat shock protein 90 (Hsp90), exhibiting potential antineoplastic activity.

2-Methoxyestradiol (2-ME2) is an orally bioavailable estradiol metabolite with potential antineoplastic activity. 2-Methoxyestradiol inhibits angiogenesis by reducing endothelial cell proliferation and inducing endothelial cell apoptosis. This agent also inhibits tumor cell growth by binding to tubulin, resulting in antimitotic activity, and by inducing caspase activation, resulting in cell cycle arrest in the G2 phase, DNA fragmentation, and apoptosis.

Daprodustat (GSK1278863) is a HIF-prolyl hydroxylase inhibitor.

Demethyleneberberine, which is composed of a potential antioxidant structure, could penetrate the membrane of mitochondria and accumulate in mitochondria either in vitro or in vivo.Demethyleneberberine suppresses CYP2E1, hypoxia inducible factor α, and inducible nitric oxide synthase, which contributes to oxidative stress and restored sirtuin 1 AMP-activated protein kinase peroxisome proliferator-activated receptor-γ coactivator-1α pathway-associated fatty acid oxidation in chronic ethanol-fed mice.

Oltipraz (RP 35972) is a synthetic dithiolethione with potential chemopreventive and anti-angiogenic properties. Oltipraz induces phase II detoxification enzymes, such as glutathione S transferase (GST) and NAD(P)H: quinone oxidoreductase 1 (NQO1). The induction of detoxification enzymes enhances the detoxification of certain cancer-causing agents, thereby enhancing their elimination and preventing carcinogen-induced DNA damages. Although the exact mechanism through which the anti-angiogenesis effect remains to be fully elucidated, oltipraz maybe able to modulate the expression of a number of angiogenic factors, thereby blocking the sustained and focal neovascularization in multiple tumor cell types.

Vadadustat is a novel, titratable, oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor in development for the treatment of anemia.

BAY 87-2243 is a potent and selective inhibitor of hypoxia-inducible factor-1 (HIF-1).

EL-102 is a HIF1α inhibitor with anticancer activity that inhibits microtubule protein polymerization and can be used to study prostate cancer.

Cephaeline was highly active against protected primary CLL cells (relative IC50's 35nM ) and acted by repressing HIF-1α± and disturbing intracellular redox homeostasis.

KC7F2 is a potent HIF-1 pathway inhibitor with potential anti-cancer activity.

HIF-1α-IN-2 is a novel and highly potent HIF-1α inhibitor with anticancer and antitumor activity that inhibits the expression of HIF-1α and VEGF in a dose-dependent manner and inhibits cell migration.

Sodium Aescinate (Escin sodium salt) is extracted from Aesculus wilsonii.

IDF-11774 is a HIF-1 inhibitor.It reduces hif-1α HRE luciferase activity (IC50 = 3.65 μM).

VH-298 is a potent inhibitor of VHL that stabilizes HIF-α and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-α protein-protein interaction downstream of HIF-α hydroxylation by PHD enzymes.

Lificiguat (YC-1) is an nitric oxide (NO)-independent activator of soluble guanylyl cyclase(sGC) and an inhibitor of Hypoxia-inducible factor-1alpha (HIF-1alpha).

ML228 is a potent the Hypoxia Inducible Factor (HIF) pathway activator with EC50 of 1 μM. ML228 potently activates HIF in vitro as well as its downstream target VEGF.

1. Cinnamaldehyde (Cinnamic Aldehyde) has antipyretic activity. 2. Cinnamaldehyde is a sedative agent. 3. Cinnamaldehyde inhibits invasive capabilities of MDA-MB-435S cells was correlated with down-regulating the expression of miR-27a. 4. Cinnamaldehyde induces the generation of reactive oxygen species and exerts vasodilator and anticancer effects. 5. Cinnamaldehyde appears to be a promising candidate as an adjuvant in combination therapy with 5-fluorouracil (5-FU) and oxaliplatin (OXA), two chemotherapeutic agents used in CRC treatment. The possible mechanisms of its action may involve the regulation of drugmetabolizing genes. 6. Cinnamaldehyde plays a certain role in inhibiting the occurrence and progression of melanoma and its action mechanism may be manifested by inhibiting expression of VEGF and HIF-α, thus blood vessel simulation and formation of new blood vessels of melanoma cells, and growth of tumors accordingly.

Acriflavine Hydrochloride (Acriflavine HCl) is a HIF-1α inhibitor. It acts by targeting HIF-1α-mediated pathways and decreasing the level of PGK1, VEGF, and HIF-1α in vitro and in vivo.

THS-044 (N-[2-Nitro-4-(Trifluoromethyl)phenyl]morpholin-4-Amine) binding stabilizes the HIF2α PAS-B folded state with a kd of 2 μM and regulates HIF2 activity in endogenous and clinical settings.

Pantoprazole sodium (Pantecta) is the sodium salt form of a substituted benzimidazole with proton pump inhibitor activity. Pantoprazole sodium is a lipophilic, weak base that crosses the parietal cell membrane and enters the acidic parietal cell canaliculus where it becomes protonated, producing the active metabolite sulfenamide, which forms an irreversible covalent bond with two sites of the H+ K+-ATPase enzyme located on the gastric parietal cell, thereby inhibiting both basal and stimulated gastric acid production.

M1002 is a hypoxia-inducible factor-2 (HIF-2) agonist that enhances the affinity of HIF-2alpha and ARNT for transcriptional activation. It alters the Tyr2 conformation of the HIF-2alpha PAS-B structural domain and acts synergistically with inhibitors of the prolyl hydroxylase structural domain (PHD).

AKB-6899 is an inhibitor of prolyl hydroxylase domain 3 (PHD3) and increases the soluble form of the VEGF receptor (sVEGFR-1) production from GM-CSF-treated macrophages. AKB-6899 leads to stabilization of HIF-2α which induces sVEGFR-1 production from tumor-associated macrophages and decreases tumor growth.

HIF-IN-1 is a potent inhibitor of hypoxia-inducible factor (HIF-1), which is associated with tumor and cancer cell proliferation and inhibits HIF-1α protein aggregation.

HIF-1 inhibitor-4 (HIF-1 inhibitor-4) is a HIF-1 inhibitor with IC50 of 560 nM. HIF-1 inhibitor-4 reduces the HIF-1α protein level without affecting its mRNA level.

Acetylarenobufagin is a steroidal hypoxia-inducible factor-1 (HIF-1) modulator.

HIF-2α agonist 2 is an HIF-2α agonist with an EC50 value of 1.68 μM for HIF-2α. HIF-2α agonist 2 can promote the stability of the ARNT A B ring in the 3z structure of HIF-2a-ARNT complex without cytotoxicity to 786-o-Reha-Luc cells. HIF-2α agonist 2 can be used in the study of oxygen metabolism and is closely related to the occurrence of cancer.

FM19G11 is an inhibitor of hypoxia inducible factor (HIF) α-subunit (IC50 = 80 nM in hypoxia induced luciferase assay).

SYP-5 is a novel inhibitor of HIF-1, suppresses tumor cells invasion and angiogenesis.

KG-548 is a dual inhibitor of ARNT TACC3 and HIF-1α, binding to the β-fold surface involved in HIF-2 dimerization and coactivator recruitment, inhibiting lactate production and useful in cancer research.

Hydroxycitric acid tripotassium hydrate (Potassium citrate monohydrate) is the major active ingredient of Garcinia cambogia and a derivative of citric acid, which effectively inhibits stone formation and HIF, and has antioxidation, anti-inflammation, and anti-tumor effects. It also competitively inhibits ATP citrate lyase, offering weight loss benefits.

25(R,S)-Ruscogenin is a natual product.

M1001 is a HIF-2α agonist.

2,4-DPD is competitive inhibitor of the oxygen-sensing enzyme HIF-α prolyl hydroxylase (HIF-PH)

Adaptaquin is an inhibitor of the hypoxia-inducing factor prolyl hydroxylase (HIF-PH) [1] [2].

ZINC13466751 is a potent HIF-1α von Hippel-Lindau interaction inhibitor(IC50 of 2.0 µM).

Naphthofluorescein (Naphthafluorescein) is a Mint3 inhibitor with potential antitumor and anti-inflammatory activities, inhibits the interaction between HIF-1 and Mint3, inhibits Mint3-dependent HIF-1 activity, and inhibits glycolytic activity in cancer cells and macrophages without showing significant in vitro cytotoxicity or in vivo side effects. Naphthofluorescein is also a fluorescent pH-sensitive probe for functional Cherenkov imaging.