2-Oxoglutarate analogue inhibitors of hif prolyl hydroxylase
Abstract
Hydroxylation of hypoxia-inducible factor, a nuclear transcription factor, is catalysed by iron and 2-oxoglutarate dependent hydroxylases. Various analogues of the 2-oxoglutarate cosubstrate were synthesised and shown to inhibit the activity of human hypoxia-inducible factor-1alpha prolyl hydroxylases in cell-free extracts.
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R-2HG weakly inhibited PHD2 and BBOX1, with IC50 values of approximately 7 mM and 13 mM, respectively.
“By contrast, inhibition of PHD2 and BBOX1 by R-2HG was weak, with IC 50 values of approximately 7 and 13 mM, respectively, consistent with previous work with the PHDs (Mole et al, 2003).”
From The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases (2011) · cites this paper as Mole et al, 2003
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“Moreover, DMOG was unable to enhance the survival effect of hypoxia and was effective at 100 M, which compares with maximal effects in tissue culture cells at 1 mM (28, 29).”
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“Indeed, a number of PHD inhibitors have been described, including direct inhibitors of the PHDs [31–32], analogs of naturally occurring cyclic hydroxamates [23], as well as antagonists of α-ketoglutarate [29].”
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“The pharmacologic pan-hydroxylase inhibitor dimethyloxalylglycine (DMOG) is a widely used 2-OG mimetic which suppresses the activity of both proline and asparaginyl hydroxylases in vivo and in vitro [46].”
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“It has also become clear that members of this family can be directly inhibited with drug-like small molecules that bind to their catalytic sites and interfere with 2-oxogluta- rate binding, iron binding, or both (Ivan et al. 2002; Mole et al. 2003; Schlemminger et al. 2003; Safran et al. 2006).”
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“These enzymes C can be inhibited with drug-like small molecules that compete with 2-oxoglutarate or interfere with iron utilization, both in vitro and in vivo (Bruegge et al., 2007; Mole et al., 2003; Ozer and Bruick, 2007; Safran et al., 2006).”
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“Attempts to discover and develop more specific and safe HIF-PH inhibitors have been described (Mole et al., 2003).”
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“2003), as well as antagonists of α-keto-glutarate (Mole et al. 2003).”
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“In addition to manipulating the oxygen tension, we have used the pharmacological inhibitors dimethyloxalylglycine (DMOG) and JNJ-42041935 (abbreviated to JNJ1935 in this study), both of which are cell permeable 2-oxoglutarate analogues which inhibit the hydroxylation of HIF-1a by displacing the endogenous 2- oxoglutar…”
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“HIF activity is quickly decreased posttranslationally by HIF prolyl hydroxylase domain proteins (HIF PHDs), which hydroxylate the alpha subunit of the HIF heterodimer at Pro-402 or Pro564 within the C-terminal oxygen-dependent degradation domain to make it a substrate of the von Hippel Lindau protein, an E3 ubiquitin…”
BackgroundProlyl hydroxylase inhibition during hyperoxia prevents oxygen-induced retinopathy
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“Inhibition of PHD can be induced by oxoglutarate analogues, such as dimethyloxalylglycine (DMOG), which competitively inhibit the hydroxylation of HIF-1/2 by displacing the endogenous oxoglutarate cofactor (13, 14).”
BackgroundWillam, C., Maxwell, P. H., Nichols, L., Lygate, C. A., Tian, Y., Bernhardt, W. M., Wiesener, M. S., Ratcliffe, P. J., Eckardt, K., & Pugh, C. W. (2006) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2006.04.009 · Cited by 111 · see citing works
“There is increasing interest in the possibility of using PHD specific inhibitors to manipulate the HIF system for therapeutic gain [11,13,28–30].”
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“Current studies are underway to determine the contribution of these proteins to the salubrious effects of global PHD inhibitors (Mole et al, 2003; Mecinovic et al, 2009; Rose et al, 2010, 2011; McDonough et al, 2005).”
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“Recently, a hypoxia-responsive element was identified in the 6-phosphofructo2-kinase/fructose-2,6-bisphosphatase genes PFKFB-4 and PFKFB-3 (Minchenko et al., 2004; Fukasawa et al., 2004; Obach et al., 2004).”
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“2) (Cunliffe et al., 1992; Mole et al., 2003; Hausinger, 2004).”
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“Therefore, inhibition of PHD activity by hypoxia, oxoglutarate analogues [61], or iron chelators [62] leads to the stabilization of HIF-1α.”
BackgroundDiabetic nephropathy: a disorder of oxygen metabolism?
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Self-citationSTAT3 and HIF1α cooperatively mediate the transcriptional and physiological responses to hypoxia
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“…5% oxygen tension, while pseudohypoxia was forced by using either dimethyloxalylglycine (DMOG), an inhibitor of Phd-dependent degradation of Hif1α (Mole et al., 2003); CoCl2 or dexamethasone (Dex),a synthetic glucocorticoid that contributes to the stabilization of Hif1α by degrading Vhl (Vettori…”
MethodDeng, A., Arndt, M. A., Satriano, J. A., Singh, P., Rieg, T., Thomson, S. C., Tang, T., & Blantz, R. C. (2010) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00153.2010 · Cited by 71 · see citing works
Glucose Metabolism and Oxygen Availability Govern Reactivation of the Latent Human Retrovirus HTLV-1
Kulkarni, A., Mateus, M., Thinnes, C. C., McCullagh, J., Schofield, C. J., Taylor, G. P., & Bangham, C. R. M. (2017) · Cell chemical biology · doi:10.1016/j.chembiol.2017.08.016 · Cited by 70 · see citing works
“Compared with control cells, DMOG-treated infected PBMCs also showed a significant upregulation in positive control VEGF transcription, signifying HIF stabilization in DMOG-treated cells (Figure 2C) and consistent with the use of DMOG as an experimental mimic of hypoxia (Mole et al., 2003).”
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Natural Product-Derived Small Molecule Activators of Hypoxia-Inducible Factor-1 (HIF-1)
Nagle, D. G., & Zhou, Y. (2006) · Current Pharmaceutical Design · doi:10.2174/138161206777698783 · Cited by 68 · see citing works
“A structure-activity relationship study conducted using a cell-free assay system identified a number of additional 2OG analogues that inhibit HPHs [46].”
BackgroundWu, D., Harrison, D. L., Szasz, T., Yeh, C., Shentu, T., Meliton, A. Y., Huang, R., Zhou, Z., Mutlu, G. M., Huang, J., et al. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00390-y · Cited by 66 · see citing works
Cellular oxygen sensing in health and disease
Mole, D. R., & Ratcliffe, P. J. (2007) · Pediatric Nephrology · doi:10.1007/s00467-007-0632-x · Cited by 66 · see citing works
Self-citationBenzimidazole-2-pyrazole HIF Prolyl 4-Hydroxylase Inhibitors as Oral Erythropoietin Secretagogues
Rosen, M. D., Venkatesan, H., Peltier, H. M., Bembenek, S. D., Kanelakis, K. C., Zhao, L. X., Leonard, B. E., Hocutt, F. M., Wu, X., Palomino, H. L., et al. (2010) · ACS Medicinal Chemistry Letters · doi:10.1021/ml100198y · Cited by 64 · see citing works
A novel series of imidazo[1,2-a]pyridine derivatives as HIF-1α prolyl hydroxylase inhibitors
Warshakoon, N. C., Wu, S., Boyer, A. S., Kawamoto, R. M., Sheville, J., Renock, S., Xu, K., Pokross, M. E., Evdokimov, A. G., Walter, R., et al. (2006) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2006.08.089 · Cited by 63 · see citing works
Reporter Ligand NMR Screening Method for 2-Oxoglutarate Oxygenase Inhibitors
Leung, I. K. H., Demetriades, M., Hardy, A., Lejeune, C., Smart, T. J., Szöllössi, A., Kawamura, A., Schofield, C. J., & Claridge, T. D. W. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm301583m · Cited by 62 · see citing works
Self-citationWarshakoon, N. C., Wu, S., Boyer, A. S., Kawamoto, R. M., Sheville, J., Renock, S., Xu, K., Pokross, M. E., Zhou, S., Winter, C., et al. (2006) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2006.08.040 · Cited by 56 · see citing works
HIF-1α inhibitors: Synthesis and biological evaluation of novel moracin O and P analogues
Xia, Y., Jin, Y., Kaur, N., Choi, Y., & Lee, K. (2011) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2011.03.022 · Cited by 56 · see citing works
Jahangir, S., Hosseini, S., Mostafaei, F., Sayahpour, F. A., & Eslaminejad, M. B. (2018) · Journal of Materials Science Materials in Medicine · doi:10.1007/s10856-018-6202-x · Cited by 55 · see citing works
Vogler, M., Vogel, S., Krull, S., Farhat, K., Leisering, P., Lutz, S., Wuertz, C. M., Katschinski, D. M., & Zieseniß, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0069128 · Cited by 54 · see citing works
“To gain further insight into the interrelationship between HIF-1 and the observed morphological changes in L929 cells we inhibited the enzymatic activity of the PHDs using the oxoglutarate analog dimethyloxalylglycine (DMOG) [27].”
MethodInfluentialSingh, C., Hoppe, G., Tran, V., McCollum, L., Bolok, Y., Song, W., Sharma, A., Brunengraber, H., & Sears, J. E. (2019) · JCI Insight · doi:10.1172/jci.insight.129398 · Cited by 53 · see citing works
“Inhibition of dioxygenases even in hyperoxia can be induced using small-molecule carbonyl glycines that are antagonistic, competitive α-KG analogs (22, 23).”
BackgroundMetabolic regulation of intestinal epithelial barrier during inflammation
Colgan, S. P., Curtis, V. F., Lanis, J. M., & Glover, L. E. (2014) · Tissue Barriers · doi:10.4161/21688362.2014.970936 · Cited by 49 · see citing works
Hypoxia Signaling in Parkinson’s Disease: There Is Use in Asking “What HIF?”
Pinilla, L. L., Ugun‐Klusek, A., Rutella, S., & Girolamo, L. A. D. (2021) · Biology · doi:10.3390/biology10080723 · Cited by 49 · see citing works
“Thus, high concentrations of 2-OG or its synthetic analogs such as dimethyloxalylglycine (DMOG), can inhibit PHDs and FIHs, promoting normoxic HIF-1α stabilization [18].”
BackgroundPiantadosi, C. A., & Suliman, H. B. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m709741200 · Cited by 50 · see citing works
Buisson, C., Marchand, A., Bailloux, I., Lahaussois, A., Martin, L., & Molina, A. (2016) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2016.01.029 · Cited by 49 · see citing works
Stubbs, C. J., Loenarz, C., Mecinović, J., Yeoh, K. K., Hindley, N., Liénard, B. M. R., Sobott, F., Schofield, C. J., & Flashman, E. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm900285r · Cited by 46 · see citing works
Self-citationSpégel, P., Malmgren, S., Sharoyko, V., Newsholme, P., Koeck, T., & Mulder, H. (2011) · Biochemical Journal · doi:10.1042/bj20100655 · Cited by 51 · see citing works
Tegley, C. M., Viswanadhan, V. N., Biswas, K., Frohn, M. J., Peterkin, T. A. N., Chang, C. W. T., Bürli, R. W., Dao, J. H., Veith, H., Rogers, N. E., et al. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2008.06.031 · Cited by 45 · see citing works
Targeting histone demethylase KDM5B for cancer treatment
Fu, Y.-D., Huang, M.-J., Guo, J., You, Y.-Z., Liu, H., Huang, L., & Yu, B. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112760 · Cited by 45 · see citing works
Design and synthesis of substituted pyridine derivatives as HIF-1α prolyl hydroxylase inhibitors
Warshakoon, N. C., Wu, S., Boyer, A. S., Kawamoto, R. M., Sheville, J., Bhatt, R. T., Renock, S., Xu, K., Pokross, M. E., Zhou, S., et al. (2006) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2006.08.026 · Cited by 39 · see citing works
Villar, D., Vara-Vega, A., Landázuri, M. O., & del Peso, L. (2007) · Biochemical Journal · doi:10.1042/bj20071052 · Cited by 39 · see citing works
Murray, J. K., Chenera, B., Allgeier, A. M., Kasparian, A. J., Viswanadhan, V. N., Wilde, C., Allen, J. R., Yoder, S. C., Biddlecome, G. H., Hungate, R. W., et al. (2010) · Journal of Combinatorial Chemistry · doi:10.1021/cc100073a · Cited by 38 · see citing works
Current Understanding of HIF in Renal Disease
Rosenberger, C., Rosen, S., & Heyman, S. N. (2005) · Kidney & Blood Pressure Research · doi:10.1159/000090187 · Cited by 36 · see citing works
“meaning that transcriptional activity occurs in more extreme degrees of hypoxia than the inhibition of HIF degradation. PHD and FIH action sites are schematically outlined in figure 1 . PHD-blockade forms an attractive target for pharmacologic HIF induction. Iron chelators (like desferrioxamine [DFX]) and transition m…”
BackgroundMinchenko, O. H., Opentanova, I. L., Ogura, T., Minchenko, D. O., Комісаренко, С. В., Caro, J., & Esumi, H. (2005) · Acta Biochimica Polonica · doi:10.18388/abp.2005_3402 · Cited by 33 · see citing works
“This reaction is mediated by specific irondependent prolyl hydroxylases that utilize oxoglutarate as a co-substrate (Epstein et al., 2001; Lando et al., 2002; Mole et al., 2003; Schofield & Ratcliffe, 2004).”
BackgroundDual-action inhibitors of HIF prolyl hydroxylases that induce binding of a second iron ion
Yeoh, K. K., Chan, M. C., Thalhammer, A., Demetriades, M., Chowdhury, R., Tian, Y., Stolze, I. P., McNeill, L. A., Lee, M. K., Woon, E. C. Y., et al. (2012) · Organic & Biomolecular Chemistry · doi:10.1039/c2ob26648b · Cited by 34 · see citing works
Self-citationThe inhibition of factor inhibiting hypoxia-inducible factor (FIH) by β-oxocarboxylic acids
Banerji, B., Conejo‐García, A., McNeill, L. A., McDonough, M. A., Buck, M. R., Hewitson, K. S., Oldham, N. J., & Schofield, C. J. (2005) · Chemical Communications · doi:10.1039/b510707e · Cited by 33 · see citing works
Self-citationUPLC–MS-Based Procedures to Detect Prolyl-Hydroxylase Inhibitors of HIF in Urine
Mazzarino, M., Perretti, I., Stacchini, C., Comunità, F., de la Torre, X., & Botrè, F. (2020) · Journal of Analytical Toxicology · doi:10.1093/jat/bkaa055 · Cited by 31 · see citing works
Stoehr, A., Yang, Y., Patel, S., Evangelista, A. M., Aponte, A. M., Wang, G., Liu, P., Boylston, J. A., Kloner, P. H., Lin, Y., et al. (2016) · Cardiovascular Research · doi:10.1093/cvr/cvw081 · Cited by 29 · see citing works
“DMOG is metabolized to NOG, which acts as a competitive inhibitor of a-ketoglutarate-dependent hydroxylases.(22) – 24 We found that inhibition of a-ketoglutarate-dependent hydroxylases increased the stability of a large number of proteins and reduced the rate of protein synthesis.”
BackgroundSkarpos, H., Vorob’eva, D. V., Osipov, S. N., Odinets, I. L., Breuer, E., & Röschenthaler, G. (2006) · Organic & Biomolecular Chemistry · doi:10.1039/b607060d · Cited by 30 · see citing works
Using NMR Solvent Water Relaxation to Investigate Metalloenzyme−Ligand Binding Interactions
Leung, I. K. H., Flashman, E., Yeoh, K. K., Schofield, C. J., & Claridge, T. D. W. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm901537q · Cited by 29 · see citing works
Self-citationA fluorescence polarization-based interaction assay for hypoxia-inducible factor prolyl hydroxylases
Cho, H.-J., Park, H., & Yang, E. G. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.09.041 · Cited by 29 · see citing works
Boovanahalli, S. K., Jin, X., Jin, Y., Kim, J. H., Đạt, N. T., Hong, Y., Lee, J. H., Jung, S., Lee, K., & Lee, J. J. (2007) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2007.09.005 · Cited by 29 · see citing works
Catalytic mechanism and substrate specificity of HIF prolyl hydroxylases
Smirnova, N. A., Hushpulian, D. M., Speer, R. E., Gaisina, I. N., Ratan, R. R., & Gazaryan, I. G. (2012) · Biochemistry (Moscow) · doi:10.1134/s0006297912100033 · Cited by 29 · see citing works
Thevis, M., Kohler, M., Schlörer, N. E., & Schänzer, W. (2007) · Journal of the American Society for Mass Spectrometry · doi:10.1016/j.jasms.2007.11.003 · Cited by 29 · see citing works
“Derivatives of 2-oxoglutarate [18, 19], hydroxyanthraquinones [20], 5-acyl sulfonamides [21], dihydroxybenzoates [22], hydroxyquinolines [23], pyrazolopyridines [24], andmany other compounds [25–28]were Address reprint requests to Dr.”
BackgroundWeirath, N. A., Hurben, A. K., Chao, C., Pujari, S. S., Cheng, T., Liu, S., & Tretyakova, N. Y. (2022) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.1c00677 · Cited by 28 · see citing works
Tang, K., Jiao, L.-M., Qi, Y., Wang, T., Li, Y., Xu, J., Wang, Z., Yu, B., Liu, H., & Zhao, W. H. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00797 · Cited by 28 · see citing works
2-Oxoglutarate analogue inhibitors of prolyl hydroxylase domain 2
Mecinović, J., Loenarz, C., Chowdhury, R., & Schofield, C. J. (2009) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2009.09.005 · Cited by 28 · see citing works
Self-citationImplications of Protein Post-Translational Modifications in IBD
Ehrentraut, S., & Colgan, S. P. (2012) · Inflammatory Bowel Diseases · doi:10.1002/ibd.22859 · Cited by 24 · see citing works
“The identification of HIF-selective PHDs has provided unique opportunities for the development of PHDbased therapies.(88,89) While there is wide interest in devel-”
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Hagos, Y., Schley, G., Schödel, J., Krick, W., Burckhardt, G., Willam, C., & Burckhardt, B. C. (2012) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-012-1140-9 · Cited by 21 · see citing works
“Analogs of αKG and citric acid cycle intermediates were developed as potential drugs to inhibit the PHDs and thereby allow the function of HIF even in the presence of oxygen in cell culture [17, 20] as well as in animal studies of acute renal failure [3] and chronic kidney disease [22, 26].”
BackgroundLocal pharmacological induction of angiogenesis: Drugs for cells and cells as drugs
Gaspar, D., Peixoto, R., Pieri, A. D., Striegl, B., Zeugolis, D. I., & Raghunath, M. (2019) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2019.06.002 · Cited by 21 · see citing works
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“G Western blot analysis of phosphorylation levels of proteins indicated from cultured aSMCs treated with PHD inhibitor DMOG or DMSO (control), n = 3 independent experiments.”
MethodInfluentialThymosin β4 promotes autophagy and repair via HIF-1α stabilization in chronic granulomatous disease
Renga, G., Oikonomou, V., Moretti, S., Stincardini, C., Bellet, M. M., Pariano, M., Bartoli, A., Brancorsini, S., Mosci, P., Finocchi, A., et al. (2019) · Life Science Alliance · doi:10.26508/lsa.201900432 · Cited by 17 · see citing works
“…mice with aspergillosis with dimethyloxalylglycine (DMOG)—a cell-permeable competitive inhibitor of prolyl hydroxylase (PHD) that stabilizes HIF-1α (Mole et al, 2003)—for 5 d. Similar to Tβ4, DMOG reduced fungal burden (Fig 5A), ameliorated lung pathology (Fig 5B), increased HIF-1α expression…”
BackgroundTargeting hypoxia in inflammatory bowel disease
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- Authors
- Mole, D. R., Schlemminger, I., McNeill, L. A., Hewitson, K. S., Pugh, C. W., Ratcliffe, P. J., & Schofield, C. J.
- Affiliations
- Centre for Human Genetics (GB)
- University of Oxford (GB)
- Corresponding author
- Schofield, Christopher J
- Venue
- Bioorganic & Medicinal Chemistry Letters
- Publisher
- Elsevier BV
- Published
- 2003-08
- Volume
- 13
- Issue
- 16
- Pages
- 2677-2680
- ISSN
- 0960-894X (ISSN-L)
- OpenAlex
- W2007522021
- Cited by
- 145
- References
- 28
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 5 · 2022: 6 · 2021: 3 · 2020: 9 · 2019: 6 · 2018: 7 · 2017: 7 · 2016: 8 · 2015: 3 · 2014: 5 · 2013: 6 · 2012: 10
- FWCI
- 2.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Bioorganic & Medicinal Chemistry Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Deutscher Akademischer Austauschdienst
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- prolyl hydroxylase inhibitors, hypoxia-inducible factor-1α, HIF-1α hydroxylation, enzyme inhibition, hypoxia
- MeSH terms
- Catalysis, Cell-Free System, Enzyme Inhibitors, Humans, Iron, Iron Chelating Agents, Isoenzymes, Ketoglutaric Acids, Procollagen-Proline Dioxygenase, Transcription Factors, Molecular Structure, Hypoxia-Inducible Factor 1, alpha Subunit
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