Recent Advances in Developing Inhibitors for Hypoxia-Inducible Factor Prolyl Hydroxylases and Their Therapeutic Implications

Kim, So Yeon; Yang, Eun Gyeong

doi:10.3390/molecules201119717

Cited by 59 publications

(34 citation statements)

References 93 publications

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“…K m values determined under these conditions are consistent with the ones previously published [6][7][8][9][10] and are not significantly different across all the PHD isotypes used in the present study: 0.31, 0.98, 0.66, and 0.56 μM for PHD1, 2, 3, and FIH1 respectively. In addition, we have shown that these compounds are reversible inhibitors for PHD2.…”

Section: K M For 2-og Reversibility and Mechanism Of Inhibitionsupporting

confidence: 92%

“…The modulation of the activity of these enzymes could be beneficial for the treatment of a variety of diseases, therefore, a large number of PHD2 inhibitors have been developed and are now in late stage clinical trials for the treatment of anemia and chronic kidney diseases [8][9][10][11][12][13]. Several companies have reported PHD inhibitors in clinical development for the treatment of ischemia and anemia associated with chronic renal disease.…”

Section: Discussionmentioning

confidence: 99%

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Time-dependent inhibition of PHD2

et al. 2017

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Prolyl hydroxylases (PHDs) down-regulate the level of hypoxia-inducible factors (HIFs) by hydroxylating key proline residues that trigger the degradation of the protein and affect the cell and its ability to respond to hypoxic stress. Several small molecule PHD inhibitors are now in various preclinical and clinical stages for the treatment of anemia. The present study provides a detail kinetic analysis for some of these inhibitors. The data generated in the present study suggest that these compounds are reversible and compete directly with the co-substrate, 2-oxoglutarate (2-OG) for binding at the enzyme active site. Most of these compounds are pan PHD inhibitors and exhibit a time-dependent inhibition (TDI) mechanism due to an extremely slow dissociation rate constant, k off , and a long residence time.

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Section: K M For 2-og Reversibility and Mechanism Of Inhibitionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Time-dependent inhibition of PHD2

et al. 2017

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“…Stable HIF1α dimerizes with the constitutively expressed b subunit to activate genes with hypoxia-response elements (HREs) in their promoters (14, 15). No HIF-1-specific inhibitors currently exist, so targeting its vital transcriptional targets and the enzymes that regulate HIF-1 activity are promising ways to modulate hypoxia signaling in cancer cells (15, 16). …”

Section: Introductionmentioning

confidence: 99%

Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models

Logsdon

Grimard

Luo

et al. 2016

Molecular Cancer Therapeutics

133

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Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related mortality in the United States. Aggressive treatment regimens have not changed the disease course, and the median survival has just recently reached a year. Several mechanisms are proposed to play a role in PDAC therapeutic resistance, including hypoxia, which creates a more aggressive phenotype with increased metastatic potential and impaired therapeutic efficacy. AP Endonuclease-1/Redox Effector Factor 1 (APE1/Ref-1) is a multi-functional protein possessing a DNA repair function in base excision repair and the ability to reduce oxidized transcription factors, enabling them to bind to their DNA target sequences. APE1/Ref-1 regulates several transcription factors involved in survival mechanisms, tumor growth, and hypoxia signaling. Here, we explore the mechanisms underlying PDAC cell responses to hypoxia and modulation of APE1/Ref-1 redox signaling activity, which regulates the transcriptional activation of hypoxia inducible factor 1 alpha (HIF1α). Carbonic anhydrase IX (CA9) is regulated by HIF1α and functions as part of the cellular response to hypoxia to regulate intracellular pH, thereby promoting cell survival. We hypothesized that modulating APE1/Ref-1 function will block activation of downstream transcription factors, STAT3 and HIF1α, interfering with hypoxia-induced gene expression. We demonstrate APE1/Ref-1 inhibition in patient-derived and established PDAC cells results in decreased HIF1α–mediated induction of CA9. Furthermore, an ex vivo 3D tumor co-culture model demonstrates dramatic enhancement of APE1/Ref-1-induced cell killing upon dual-targeting of APE1/Ref-1 and CA9. Both APE1/Ref-1 and CA9 are under clinical development, therefore these studies have the potential to direct novel PDAC therapeutic treatment.

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“…Over the last few years in-depth work has therefore been made to find PHD inhibitors by several means, such as in silico drug screening [67], combinatorial libraries [68] and high-throughput screening [69]. These efforts have led to the discovery of several compounds, four of which are currently being tested in human clinical trials [70]. …”

Section: Introductionmentioning

confidence: 99%

New Insights into Protein Hydroxylation and Its Important Role in Human Diseases

Zurlo

Guo

Takada

et al. 2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Protein hydroxylation is a post-translational modification catalyzed by 2-oxoglutarate-dependent dioxygenases. The hydroxylation modification can take place on various amino acids, including but not limited to proline, lysine, asparagine, aspartate and histidine. A classical example of this modification is hypoxia inducible factor alpha (HIF-α) prolyl hydroxylation, which affects HIF-α protein stability via the Von-Hippel Lindau (VHL) tumor suppressor pathway, a Cullin 2-based E3 ligase adaptor protein frequently mutated in kidney cancer. In addition to protein stability regulation, protein hydroxylation may influence other post-translational modifications or the kinase activity of the modified protein (such as Akt and DYRK1A/B). In other cases, protein hydroxylation may alter protein-protein interaction and its downstream signaling events in vivo (such as OTUB1, MAPK6 and eEF2K). In this review, we highlight the recently identified protein hydroxylation targets and their pathophysiological roles, especially in cancer settings. Better understanding of protein hydroxylation will help identify novel therapeutic targets and their regulation mechanisms to foster development of more effective treatment strategies for various human cancers.

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Recent Advances in Developing Inhibitors for Hypoxia-Inducible Factor Prolyl Hydroxylases and Their Therapeutic Implications

Cited by 59 publications

References 93 publications

Time-dependent inhibition of PHD2

Time-dependent inhibition of PHD2

Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models

New Insights into Protein Hydroxylation and Its Important Role in Human Diseases

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