Prolyl hydroxylase domain-containing protein inhibitors as stabilizers of hypoxia-inducible factor: small molecule-based therapeutics for anemia

Yan, Lin; Colandrea, Vincent J.; Hale, Jeffrey J.

doi:10.1517/13543776.2010.510836

Cited by 80 publications

(90 citation statements)

References 133 publications

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“…Small molecule PHD inhibitors have been demonstrated to be promising in strategies for treating diseases related to hypoxic adaptation like anemia, stroke, or myocardial infarction (14,35,36). The concept of cardiac tissue protection is delineated from several recent preclinical studies.…”

Section: Discussionmentioning

confidence: 99%

Cardiomyocyte-specific Prolyl-4-hydroxylase Domain 2 Knock Out Protects from Acute Myocardial Ischemic Injury

Hölscher

Silter

Krull

et al. 2011

Journal of Biological Chemistry

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Prolylhydroxylase domain proteins (PHD) are cellular oxygen-sensing molecules that regulate the stability of the ␣-subunit of the transcription factor hypoxia inducible factor (HIF)-1. HIF-1 affects cardiac development as well as adaptation of the heart toward increased pressure overload or myocardial infarction. We have disrupted PHD2 in cardiomyocytes (cPhd ؊/؊ ) When oxygen availability is impaired, the resulting hypoxia activates homeostatic mechanisms at the systemic and cellular level (1). Hypoxia-inducible factors (HIFs) 2 are essential players in these responses because they regulate the transcription of a large number of genes that affect a myriad of cellular processes, including angiogenesis, metabolism, cell survival, and oxygen delivery (2). HIF is a heterodimeric protein comprising the oxygen-sensitive ␣-subunit HIF-1␣ or the more cell type-specifically expressed HIF-2␣ or HIF-3␣ and the oxygen-insensitive ␤-subunit (3). In the presence of oxygen, HIF␣ becomes hydroxylated at two critical proline residues by prolylhydroxylase domain (PHD) enzymes (4, 5). The PHD protein family responsible for HIF␣ regulation consists of three members called prolylhydroxylase domain (PHD)1, PHD2, and PHD3 (6, 7). Following prolyl-4-hydroxylation of the critical prolyl residues under normoxic conditions, the ubiquitin ligase von Hippel-Lindau tumor suppressor protein recognizes ⌯⌱F-1␣ subunits and targets them for rapid ubiquitination and proteasomal degradation (8 -10).Based on the ubiquitous expression pattern and its dominant effect in normoxia, it had to be assumed that PHD2 is the most critical HIF-1␣-regulating PHD isoform in most tissues (11)(12)(13). This notion, learned from in vitro studies, was confirmed by the up to now available genetically modified Phd2 mouse models (14). Phd2 knock-out embryos die between embryonic day (E) 12.5 and E14.5 (15). This time point coincides with the increased levels of PHD2 in wild-type (wt) mice starting from E9.0. A major role of PHD2 in regulating the HIF system is further underscored by mouse models with a somatic Phd2 Ϫ/Ϫ knock out, which enable to analyze the in vivo function of PHD2 in the adult mice. Two independent inducible Phd2 Ϫ/Ϫ mouse models were developed by Takeda et al. (16) and Minamishima et al. (17). The phenotype of these mice most obviously resembles the consequences of HIF␣ overexpression with increased angiogenesis, erythropoiesis, and extramedullar hematopoiesis (17,18). Most interestingly, these mice also develop a cardiac phenotype with symptoms of dilated cardiomyopathy. In the heart, HIF-1␣ and thereby also the PHDs are known to influence key components of heart development, morphogenesis, and function (19,20). Long term activation of HIF-1␣ in the heart seems to activate detrimental pathways resulting in the development of heart failure (21). Thus, it is tempting to speculate that loss of PHD2 in the heart is responsible for the dilated cardiomyopathy as observed in the inducible Phd2 Ϫ/Ϫ mice. However, because these mice also develop an inc...

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Section: Discussionmentioning

confidence: 99%

Cardiomyocyte-specific Prolyl-4-hydroxylase Domain 2 Knock Out Protects from Acute Myocardial Ischemic Injury

Hölscher

Silter

Krull

et al. 2011

Journal of Biological Chemistry

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“…As shown in Figure 4, small molecule analogs of a-ketoglutarate could prevent HIF-a hydroxylation, even in well-oxygenated cells and thereby induce expression not only of endogenous Epo but also of other HIF-dependent genes that are required for robust erythropoiesis. Several companies have developed inhibitors that induce Epo and erythropoiesis in mice (Safran et al 2006;Yan et al 2010) and in humans (Yan et al 2010). Because these agents suppress expression of hepcidin (Volke et al 2009), they may be particularly effective in the treatment of anemia of chronic inflammation.…”

Section: Recent Developmentsmentioning

confidence: 99%

Erythropoietin

Bunn

2013

Cold Spring Harbor Perspectives in Medicine

211

171

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During the past century, few proteins have matched erythropoietin (Epo) in capturing the imagination of physiologists, molecular biologists, and, more recently, physicians and patients. Its appeal rests on its commanding role as the premier erythroid cytokine, the elegant mechanism underlying the regulation of its gene, and its remarkable impact as a therapeutic agent, arguably the most successful drug spawned by the revolution in recombinant DNA technology. This concise review will begin with a synopsis of the colorful history of this protein, culminating in its purification and molecular cloning. It then covers in more detail the contemporary understanding of Epo's physiology as well as its structure and interaction with its receptor. A major part of this article focuses on the regulation of the Epo gene and the discovery of HIF, a transcription factor that plays a cardinal role in molecular adaptation to hypoxia. In the concluding section, a synopsis of Epo's role in disorders of red blood cell production will be followed by an assessment of the remarkable impact of Epo therapy in the treatment of anemias, as well as concerns that provide a strong impetus for the development of even safer and more effective treatment.

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“…An inhibitor of γ-butyrobetaine hydroxylase (BBOX) is used for the treatment of cardiovascular disease [4,5] and inhibitors of the hypoxia inducible factor (HIF) prolyl hydroxylases are in clinical trials for the treatment of anaemia. [6] Inhibitors of the collagen prolyl hydroxylases have also been evaluated as potential therapeutics for the treatment of liver fibrosis. [7,8] The discovery of the JmjC domain histone demethylases, and the suggestions that some of them are potential therapeutic targets for cancer treatment, [9] Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Histone Demethylases by 4‐Carboxy‐2,2′‐Bipyridyl Compounds

et al. 2011

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# These authors contributed equally to this work. Keywordsepigenetics; histone demethylase; bipyridyl; enzyme inhibitors; 2-oxoglutarate In eukaryotes, nuclear DNA is packaged into chromatin by binding to histones and associated factors. Covalent modifications to histone tails are associated with specific transcriptional states of the associated DNA. Acetylation of lysine side-chains normally correlates with transcriptional activation, while deacetylation leads to transcriptional silencing. The regulatory roles of methylation of lysine and arginine residues appear to be more complex. Methylation of certain lysine residues is associated with active transcription, while methylation of others is associated with silencing and heterochromatin formation. Each methylation 'mark' is placed, removed and 'interpreted' in a site-specific manner by histone methyltransferases, demethylases and methyl-binding domains, respectively. The biological functions of the individual enzymes are largely undefined, and are the focus of current investigations (for review see [1,2] The JmjC histone demethylases are 2-oxoglutarate (2OG) dependent oxygenases that catalyse N ε -lysyl demethylation via hydroxylation of the methyl group in a 2-oxoglutarate and Fe(II)-dependent manner (Scheme 1). Human 2OG oxygenases catalyse a range of reactions, including hydroxylation of amino acids, DNA and small molecules, and demethylation of proteins and DNA. [3] 2OG oxygenases show promise as therapeutic targets. An inhibitor of γ-butyrobetaine hydroxylase (BBOX) is used for the treatment of cardiovascular disease [4,5] and inhibitors of the hypoxia inducible factor (HIF) prolyl hydroxylases are in clinical trials for the treatment of anaemia. [6] Inhibitors of the collagen prolyl hydroxylases have also been evaluated as potential therapeutics for the treatment of liver fibrosis. [7,8] The discovery of the JmjC domain histone demethylases, and the suggestions that some of them are potential therapeutic targets for cancer treatment, [9] Figure 1). [10][11][12][13] Compounds which catalyse the ejection of a structural Zn(II) ion from the JMJD2 demethylases have also been reported ( Figure 1). [14] In a study describing various template inhibitors of the JmjC demethylases, we found that 2,2′-bipyridyl compounds with at least one 4-carboxylate group inhibit the histone demethylase JMJD2E. [11] A related series of compounds, 5,5′-dicarboxylate-2,2′-bipyridyls, is reported to inhibit the collagen prolyl-4-hydroxylases. [15] 2,2′-Bipyridine and bipyridyl compounds have also been used as inhibitors of the HIF hydroxylases. [16] Although it is likely that in some cases the enzyme inhibition effects of bipyridyl compounds result from metal chelation in solution, they also have the potential to inhibit via active site binding, as is the case for some 2OG oxygenases; however, to date there is no structural information on their mechanism of action. Here we report structure-activity relationship studies and analyses on bipyridyl inhibitors of JMJD2E.The bipyridyl com...

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Prolyl hydroxylase domain-containing protein inhibitors as stabilizers of hypoxia-inducible factor: small molecule-based therapeutics for anemia

Abstract: Several classes of PHD enzyme inhibitors have been disclosed and several are currently in clinical trials for the development of small molecule-based therapeutics for the treatment of anemia.

Cited by 80 publications

References 133 publications

Cardiomyocyte-specific Prolyl-4-hydroxylase Domain 2 Knock Out Protects from Acute Myocardial Ischemic Injury

Cardiomyocyte-specific Prolyl-4-hydroxylase Domain 2 Knock Out Protects from Acute Myocardial Ischemic Injury

Erythropoietin

Inhibition of Histone Demethylases by 4‐Carboxy‐2,2′‐Bipyridyl Compounds

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