Application of in-vitro screening methods on hypoxia inducible factor prolyl hydroxylase inhibitors

Wu, Yue; Jiang, Zhensheng; You, Qidong; Zhang, Xiaojin

doi:10.1016/j.bmc.2017.05.026

Cited by 7 publications

(7 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For investigating the selectivity to a panel of other human 2-OG oxygenases focusing on histone N -methyl lysine demethylases (KDMs), an AlphaScreen assay was applied to determine the inhibitory rate of triazole compounds to KDMs including JMJD1A, JMJD2A, and JMJD3 (Table S2). The results indicate that the representative triazole compounds are at least 169-fold more selective for HIF-PHD2 than the KDMs, which means that these compounds are good candidates for HIF-α stabilizers.…”

Section: Resultsmentioning

confidence: 99%

Click Chemistry-Based Discovery of [3-Hydroxy-5-(1H-1,2,3-triazol-4-yl)picolinoyl]glycines as Orally Active Hypoxia-Inducing Factor Prolyl Hydroxylase Inhibitors with Favorable Safety Profiles for the Treatment of Anemia

Jiang

et al. 2018

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

As a gene associated with anemia, the erythropoiesis gene is physiologically expressed under hypoxia regulated by †hypoxia-inducing factor-α (HIF-α). Thus, stabilizing HIF-α is a potent strategy to stimulate the expression and secretion of erythropoiesis. In this study, we applied click chemistry to the discovery of HIF prolyl hydroxylase 2 (HIF-PHD2) inhibitors for the first time, and a series of triazole compounds showed preferable inhibitory activity in fluorescence polarization assays. Of particular note was the orally active HIF-PHD inhibitor 15i (IC = 62.23 nM), which was almost ten times more active than the phase III drug FG-4592 (IC = 591.4 nM). Furthermore, it can upregulate the hemoglobin of cisplatin-induced anemia mice (120 g/L) to normal levels (160 g/L) with no apparent toxicity observed in vivo. These results confirm that triazole compound 15i is a promising candidate for the treatment of renal anemia.

show abstract

Section: Resultsmentioning

confidence: 99%

Click Chemistry-Based Discovery of [3-Hydroxy-5-(1H-1,2,3-triazol-4-yl)picolinoyl]glycines as Orally Active Hypoxia-Inducing Factor Prolyl Hydroxylase Inhibitors with Favorable Safety Profiles for the Treatment of Anemia

Jiang

et al. 2018

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…MiR-21 was significantly upregulated by hypoxia/reoxygenation in HK-2 cells, while PHD2 levels decreased significantly. Hypoxia inducible transcription factor prolyl-hydroxylase 2 (HIF-PHD2) is a key regulator of the hypoxia response via hydroxylation of specific HIF-α proline residues, which may lead to the degradation of HIF-α 36 . Thus, upregulation of miR-21 and subsequent downregulation of the HIF-α suppressor PHD2 stimulates HIF-1α expression and HIF-1α-promoted glycolysis.…”

Section: Discussionmentioning

confidence: 99%

MiR-21-mediated Metabolic Alteration of Cancer-associated Fibroblasts and Its Effect on Pancreatic Cancer Cell Behavior

Chen¹,

Chen²,

Shan³

et al. 2018

Int. J. Biol. Sci.

View full text Add to dashboard Cite

In this study, we investigated whether the metabolic alteration of cancer-associated fibroblasts (CAFs) occurs via miR-21 remodeling and the effect of this alteration on pancreatic cancer cells. CAFs and normal fibroblasts (NFs) were isolated and cultured. Glucose consumption and lactic acid production were tested, and lactate dehydrogenase (LDHA), pyruvate kinase m2 (PKM2), and miR-21 expression were examined. The level of glycolysis in CAFs was determined after treatment with a miR-21 inhibitor. Primary miR-21-NC CAFs and miR-21-inhibitor CAFs were indirectly co-cultured with BxPc-3 in vitro, and the invasion capacity of these cells was determined. The aerobic oxidation index of cancer cells and the expression of succinodehydrogenase (SDH) and fumarate hydratase (FH) were assessed. Compared with NFs, CAFs showed enhanced glucose uptake capacity, lactic acid production, and elevated LDHA, PKM2, and miR-21 expression. After miR-21 inhibitor treatment, the extent of glycolysis in CAFs was reduced. After indirect co-culture with CAFs, oxidative phosphorylation and SDH, FH, and MCT expression increased in BxPc-3 cells. After co-culture with miR-21-inhibitor-CAFs, oxidative phosphorylation and invasion ability of the pancreatic cancer cells decreased. MiR-21 was involved in metabolic alteration of CAFs and affected the development of cancer cells. This metabolic alteration may be an important mechanism by which the microenvironment promotes tumor progression in a nonvascular manner.

show abstract

“…A comprehensive review has compiled the assay procedures used to screen PHD inhibitors. 55 A separate review has covered significant 2-OG derived PHD inhibitors. 50 An isoquinoline scaffold (4, Figure 5) 56 is widely used in the design of PHD inhibitors, especially in two clinical candidates, 15 (FG-2216, Figure 6) and 16 (FG-4592, roxadustat, Figure 6), discovered by FibroGen, Inc. (San Francisco, CA, U.S.).…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

“…The lack of a carboxylic acid group helps in better CNS penetration, and hence these inhibitors were considered useful in the treatment of neurological disorders. A comprehensive review has compiled the assay procedures used to screen PHD inhibitors . A separate review has covered significant 2-OG derived PHD inhibitors …”

Section: Evolution Of Medicinal Chemistry Strategies For Phd Inhibitionmentioning

confidence: 99%

Prolyl Hydroxylase Inhibitors: A Breakthrough in the Therapy of Anemia Associated with Chronic Diseases

et al. 2018

View full text Add to dashboard Cite

Chronic kidney disease, cancer, chronic inflammatory disorders, nutritional, and genetic deficiency can cause anemia. Hypoxia causes induction of hypoxia-inducible factor (HIF), which stimulates erythropoietin (EPO) synthesis. Prolyl hydroxylase domain (PHD) enzyme inhibition can stabilize hypoxia-inducible factor (HIF). HIF stabilization also decreases hepcidin, a hormone of hepatic origin, which regulates iron homeostasis. PHD inhibitors represent a novel pharmacological treatment of anemia associated with chronic diseases. Many orally active PHD inhibitors like roxadustat, molidustat, vadadustat, and desidustat are in late phase clinical trials. This review discusses the role of PHD inhibitors in the treatment of anemia associated with chronic diseases.

show abstract

Application of in-vitro screening methods on hypoxia inducible factor prolyl hydroxylase inhibitors

Cited by 7 publications

References 43 publications

Click Chemistry-Based Discovery of [3-Hydroxy-5-(1H-1,2,3-triazol-4-yl)picolinoyl]glycines as Orally Active Hypoxia-Inducing Factor Prolyl Hydroxylase Inhibitors with Favorable Safety Profiles for the Treatment of Anemia

Click Chemistry-Based Discovery of [3-Hydroxy-5-(1H-1,2,3-triazol-4-yl)picolinoyl]glycines as Orally Active Hypoxia-Inducing Factor Prolyl Hydroxylase Inhibitors with Favorable Safety Profiles for the Treatment of Anemia

MiR-21-mediated Metabolic Alteration of Cancer-associated Fibroblasts and Its Effect on Pancreatic Cancer Cell Behavior

Prolyl Hydroxylase Inhibitors: A Breakthrough in the Therapy of Anemia Associated with Chronic Diseases

Contact Info

Product

Resources

About