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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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“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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Oxygen sensing by HIF hydroxylases
Schofield, C. J., & Ratcliffe, P. J. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1366 · Cited by 2,068
Self-citationThe oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases
Chowdhury, R., Yeoh, K. K., Tian, Y., Hillringhaus, L., Bagg, E. A., Rose, N. R., Leung, I. K. H., Li, X. S., Woon, E. C. Y., Yang, M., et al. (2011) · The EMBO Reports · doi:10.1038/embor.2011.43 · Cited by 1,035
“Nevertheless, PHD2 is poorly inhibited in vitro by R-2HG (Fig 1; Table 1), and we were unable to demonstrate inhibition of the PHDs sufficient to substantially upregulate HIF in cells (Fig 3C–”
ResultInfluentialSelf-citationRegulation of glycolysis by the hypoxia-inducible factor (HIF): Implications for cellular physiology
Kierans, S. J., & Taylor, C. T. (2021) · The Journal of Physiology · doi:10.1113/jp280572 · Cited by 1,015
“deferoxamine, DFO) (Wang & Semenza, 1993), or molecules which compete for 2-oxoglutarate (Mole et al. 2003).”
BackgroundHypoxia-induced neutrophil survival is mediated by HIF-1α–dependent NF-κB activity
Walmsley, S. R., Print, C., Farahi, N., Peyssonnaux, C., Johnson, R. S., Cramer, T., Sobolewski, A., Condliffe, A. M., Cowburn, A. S., Johnson, N., et al. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20040624 · Cited by 891
“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).”
BackgroundThe use of cobalt chloride as a chemical hypoxia model
Muñoz‐Sánchez, J., & Chánez‐Cárdenas, M. E. (2018) · Journal of Applied Toxicology · doi:10.1002/jat.3749 · Cited by 535
Hypoxia: an alarm signal during intestinal inflammation
Colgan, S. P., & Taylor, C. T. (2010) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2010.39 · Cited by 461
“The identification of HIF-selective PHDs has provided unique opportunities for the development of PHD-based therapies”
BackgroundMetabolic Shifts in Immunity and Inflammation
Kominsky, D. J., Campbell, E. L., & Colgan, S. P. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0903002 · Cited by 422
Inhibition of 2-oxoglutarate dependent oxygenases
Rose, N. R., McDonough, M. A., King, O. N. F., Kawamura, A., & Schofield, C. J. (2011) · Chemical Society Reviews · doi:10.1039/c0cs00203h · Cited by 405
Self-citationTargeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases
Eltzschig, H. K., Bratton, D. L., & Colgan, S. P. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4422 · Cited by 364
Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2)
McDonough, M. A., Li, V., Flashman, E., Chowdhury, R., Mohr, C., Liénard, B. M. R., Zondlo, J., Oldham, N. J., Clifton, I. J., Lewis, J. K., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601283103 · Cited by 370
Self-citationInhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease
Fraisl, P., Aragonés, J., & Carmeliet, P. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2761 · Cited by 326
Hypoxia and gastrointestinal disease
Taylor, C. T., & Colgan, S. P. (2007) · Journal of Molecular Medicine · doi:10.1007/s00109-007-0277-z · Cited by 313
“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].”
Myllyharju, J. (2008) · Annals of Medicine · doi:10.1080/07853890801986594 · Cited by 269
Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials
Yeh, T., Leissing, T. M., Abboud, M. I., Thinnes, C. C., Atasoylu, O., Holt‐Martyn, J. P., Zhang, D., Tumber, A., Lippl, K., Lohans, C. T., et al. (2017) · Chemical Science · doi:10.1039/c7sc02103h · Cited by 247
Self-citationTargeting histone lysine demethylases — Progress, challenges, and the future
Thinnes, C. C., England, K. S., Kawamura, A., Chowdhury, R., Schofield, C. J., & Hopkinson, R. J. (2014) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2014.05.009 · Cited by 198
“The cell-penetrating dimethyl ester form of NOG, dimethyl N-oxalylglycine (DMOG), has foundwidespread applications as a hypoxia mimetic [117,118] because it inhibits both HIF prolyl and asparaginyl hydroxylases resulting in upregulation and activation respectively of the HIF system [119].”
BackgroundSelf-citationRegulation of the Hypoxia-Inducible Factor (HIF) by Pro-Inflammatory Cytokines
Malkov, M. I., Lee, C. T., & Taylor, C. T. (2021) · Cells · doi:10.3390/cells10092340 · Cited by 190
“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].”
BackgroundInhibition of endogenous HIF inactivation induces angiogenesis in ischaemic skeletal muscles of mice
Milkiewicz, M., Pugh, C. W., & Egginton, S. (2004) · The Journal of Physiology · doi:10.1113/jphysiol.2004.069757 · Cited by 165
“Characterization of the hydroxylase family involved in normoxic HIF inactivation has led to the development of inhibitors capable of HIF activation (Mole et al. 2003; Schlemminger et al. 2003).”
BackgroundSelf-citationStructural Basis for Inhibition of the Fat Mass and Obesity Associated Protein (FTO)
Aik, W. S., Demetriades, M., Hamdan, M. K. K., Bagg, E. A. L., Yeoh, K. K., Lejeune, C., Zhang, Z., McDonough, M. A., & Schofield, C. J. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm400193d · Cited by 162
Self-citationKaelin, W. G. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.010975 · Cited by 161
“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).”
Hypoxia: The Force that Drives Chronic Kidney Disease
Fu, Q., Colgan, S. P., & Shelley, C. S. (2016) · Clinical Medicine & Research · doi:10.3121/cmr.2015.1282 · Cited by 156
Rose, N. R., Woon, E. C. Y., Kingham, G. L., King, O. N. F., Mecinović, J., Clifton, I. J., Ng, S. S., Talib-Hardy, J., Oppermann, U. C. T., McDonough, M. A., et al. (2010) · Journal of Medicinal Chemistry · doi:10.1021/jm901680b · Cited by 148
Self-citationThe HIF pathway as a therapeutic target
Hewitson, K. S., & Schofield, C. J. (2004) · Drug Discovery Today · doi:10.1016/s1359-6446(04)03202-7 · Cited by 148
Self-citationControl of Cyclin D1 and Breast Tumorigenesis by the EglN2 Prolyl Hydroxylase
Zhang, Q. H., Gu, J., Li, L., Liu, J., Luo, B., Cheung, H.-W., Boehm, J. S., Ni, M., Geisen, C., Root, D. E., et al. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.09.029 · Cited by 141
“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).”
Buffet, A., Morin, A., Castro‐Vega, L. J., Habarou, F., Lussey‐Lepoutre, C., Letouzé, É., Lefèbvre, H., Guilhem, I., Haissaguerre, M., Raingeard, I., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-2463 · Cited by 137
Doege, K., Heine, S., Jensen, I., Jelkmann, W., & Metzen, E. (2005) · Blood · doi:10.1182/blood-2005-03-1138 · Cited by 128
Hypoxia and Mucosal Inflammation
Colgan, S. P., Campbell, E. L., & Kominsky, D. J. (2016) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-012615-044231 · Cited by 137
Hypoxia. 1. Intracellular sensors for oxygen and oxidative stress: novel therapeutic targets
Miyata, T., Takizawa, S., & de Strihou, C. V. Y. (2010) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00430.2010 · Cited by 131
Pharmacological targeting of the HIF hydroxylases – A new field in medicine development
Chan, M. C., Holt‐Martyn, J. P., Schofield, C. J., & Ratcliffe, P. J. (2016) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2016.01.001 · Cited by 128
Self-citationErythropoiesis‐stimulating agents and other methods to enhance oxygen transport
Elliott, S. (2008) · British Journal of Pharmacology · doi:10.1038/bjp.2008.89 · Cited by 128
“Attempts to discover and develop more specific and safe HIF-PH inhibitors have been described (Mole et al., 2003).”
BackgroundHypoxia and Metabolic Factors That Influence Inflammatory Bowel Disease Pathogenesis
Glover, L. E., & Colgan, S. P. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.01.056 · Cited by 126
Minchenko, О. H., Opentanova, I. L., Minchenko, D. O., Ogura, T., & Esumi, H. (2004) · FEBS Letters · doi:10.1016/j.febslet.2004.08.053 · Cited by 121
Adenosine and Hypoxia-Inducible Factor Signaling in Intestinal Injury and Recovery
Colgan, S. P., & Eltzschig, H. K. (2011) · Annual Review of Physiology · doi:10.1146/annurev-physiol-020911-153230 · Cited by 123
Eltzschig, H. K., MacManus, C. F., & Colgan, S. P. (2008) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2008.01.006 · Cited by 121
“2003), as well as antagonists of α-keto-glutarate (Mole et al. 2003).”
BackgroundInfluentialSelective Small Molecule Probes for the Hypoxia Inducible Factor (HIF) Prolyl Hydroxylases
Chowdhury, R., Lena, J. I. C., Chan, M. C., Greenald, D., Yeoh, K. K., Tian, Y., McDonough, M. A., Tumber, A., Rose, N. R., Conejo‐García, A., et al. (2013) · ACS Chemical Biology · doi:10.1021/cb400088q · Cited by 116
Self-citationA dynamic model of the hypoxia-inducible factor 1-alpha (HIF-1α) network
Nguyen, L. K., Cavadas, M. A. S., Scholz, C. C., Fitzpatrick, S. F., Brüning, U., Cummins, E. P., Tambuwala, M. M., Manresa, M. C., Kholodenko, B. Ν., Taylor, C. T., et al. (2013) · Journal of Cell Science · doi:10.1242/jcs.119974 · Cited by 115
“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…”
BackgroundMethodInfluentialHoppe, G., Yoon, S., Gopalan, B., Savage, A. R., Brown, R. D., Case, K. R., Vasanji, A., Chan, E. R., Silver, R. B., & Sears, J. E. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1523005113 · Cited by 118
“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
Sears, J. E., Hoppe, G., Ebrahem, Q., & Anand‐Apte, B. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0805817105 · Cited by 116
“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 112
“There is increasing interest in the possibility of using PHD specific inhibitors to manipulate the HIF system for therapeutic gain [11,13,28–30].”
BackgroundSelf-citationThe VHL Tumor Suppressor Gene: Insights into Oxygen Sensing and Cancer.
Kaelin, W. G. (2017) · Europe PMC (PubMed Central) · Cited by 111
Karuppagounder, S. S., & Ratan, R. R. (2012) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2012.28 · Cited by 97
“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).”
BackgroundBobarykina, A. Y., Minchenko, D. O., Opentanova, I. L., Moenner, M., Caro, J., Esumi, H., & Minchenko, О. H. (2006) · Acta Biochimica Polonica · doi:10.18388/abp.2006_3308 · Cited by 96
“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).”
BackgroundMechanisms of regulation of PFKFB expression in pancreatic and gastric cancer cells
Minchenko, О. H. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i38.13705 · Cited by 96
Ariazi, J. L., Duffy, K. J., Adams, D. F., Fitch, D. M., Luo, L., Pappalardi, M. B., Biju, M. P., DiFilippo, E. H., Shaw, T., Wiggall, K., et al. (2017) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.117.242503 · Cited by 94
“2) (Cunliffe et al., 1992; Mole et al., 2003; Hausinger, 2004).”
MethodNew Insights on the Genetics of Pheochromocytoma and Paraganglioma and Its Clinical Implications
Jhawar, S., Arakawa, Y., Kumar, S., Varghese, D. G., Kim, Y. S., Roper, N., Elloumi, F., Pommier, Y. G., Pacák, K., & Rivero, J. D. (2022) · Cancers · doi:10.3390/cancers14030594 · Cited by 92
Obstacles to Glioblastoma Treatment Two Decades after Temozolomide
Cruz, J. V. R., Batista, C., Afonso, B. D. H., Alexandre‐Moreira, M. S., Dubois, L. G., Pontes, B., Moura‐Neto, V., & Mendes, F. A. (2022) · Cancers · doi:10.3390/cancers14133203 · Cited by 92
Flavonoids induce HIF-1α but impair its nuclear accumulation and activity
Triantafyllou, A., Mylonis, I., Simos, G., Bonanou, S., & Tsakalof, A. K. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2007.10.050 · Cited by 87
“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?
Miyata, T., & de Strihou, C. V. Y. (2009) · Nature Reviews Nephrology · doi:10.1038/nrneph.2009.211 · Cited by 82
Structure of Human Phytanoyl-CoA 2-Hydroxylase Identifies Molecular Mechanisms of Refsum Disease*
McDonough, M. A., Kavanagh, K. L., Butler, D. S., Searls, T., Oppermann, U. C. T., & Schofield, C. J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m507528200 · Cited by 84
Self-citationSalamin, O., Kuuranne, T., Saugy, M., & Leuenberger, N. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.01.033 · Cited by 84
Iron Homeostasis and Its Interaction with Prolyl Hydroxylases
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Self-citationSTAT3 and HIF1α cooperatively mediate the transcriptional and physiological responses to hypoxia
Dinarello, A., Betto, R. M., Diamante, L., Tesoriere, A., Ghirardo, R., Cioccarelli, C., Meneghetti, G., Peron, M., Laquatra, C., Tiso, N., et al. (2023) · Cell Death Discovery · doi:10.1038/s41420-023-01507-w · Cited by 81
“…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
Glucose Metabolism and Oxygen Availability Govern Reactivation of the Latent Human Retrovirus HTLV-1
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“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).”
ResultSelf-citationMehrabani, M., Najafi, M., Kamarul, T., Mansouri, K., Iranpour, M., Nematollahi, M. H., Ghazi‐Khansari, M., & Sharifi, A. M. (2015) · Cell Proliferation · doi:10.1111/cpr.12209 · Cited by 69
Natural Product-Derived Small Molecule Activators of Hypoxia-Inducible Factor-1 (HIF-1)
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“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 68
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 67
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
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 64
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
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
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
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
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“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 56
“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 51
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 52
“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
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
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
Self-citationSpégel, P., Malmgren, S., Sharoyko, V. V., Newsholme, P., Koeck, T., & Mulder, H. (2011) · Biochemical Journal · doi:10.1042/bj20100655 · Cited by 46
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
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
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
Villar, D., Vara-Vega, A., Landázuri, M. O., & del Peso, L. (2007) · Biochemical Journal · doi:10.1042/bj20071052 · Cited by 39
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Current Understanding of HIF in Renal Disease
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“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…”
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“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
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 34
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
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“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.”
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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
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
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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 31
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
“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
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
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 30
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 25
“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
“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
Li, Z., Zhen, S., Su, K., Tumber, A., Yu, Q., Dong, Y., McDonough, M. A., Schofield, C. J., & Zhang, X. (2020) · Chemical Communications · doi:10.1039/d0cc06353c · Cited by 19
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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
“…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
Colgan, S. P. (2015) · Journal of Investigative Medicine · doi:10.1097/jim.0000000000000218 · Cited by 17
Metadata
- 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 › Heterocyclic Compound Synthesis and Bioactivity
- 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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