{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T06:49:51Z","timestamp":1791528591122,"version":"4.3.4"},"reference-count":120,"publisher":"Wiley","issue":"24","license":[{"start":{"date-parts":[[2024,11,8]],"date-time":"2024-11-08T00:00:00Z","timestamp":1731024000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["106244\/Z\/14\/Z"],"award-info":[{"award-number":["106244\/Z\/14\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C8717\/A18245"],"award-info":[{"award-number":["C8717\/A18245"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/J003018\/1"],"award-info":[{"award-number":["BB\/J003018\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/R000344\/1"],"award-info":[{"award-number":["BB\/R000344\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2024,12,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Prolyl hydroxylase domain\u2010containing proteins 1\u20133 (PHD1\u20133) are 2\u2010oxoglutarate (2OG)\u2010dependent oxygenases catalysing C\u20104 hydroxylation of prolyl residues in \u03b1\u2010subunits of the heterodimeric transcription factor hypoxia\u2010inducible factor (HIF), modifications that promote HIF\u2010\u03b1 degradation via the ubiquitin\u2010proteasome pathway. Pharmacological inhibition of the PHDs induces HIF\u2010\u03b1 stabilisation, so promoting HIF target gene transcription. PHD inhibitors are used to treat anaemia caused by chronic kidney disease (CKD) due to their ability to stimulate erythropoietin (EPO) production. We report studies on the effects of the approved PHD inhibitors Desidustat and Enarodustat, and the clinical candidate TP0463518, on activities of a representative set of isolated recombinant human 2OG oxygenases. The three molecules manifest selectivity for PHD inhibition over that of the other 2OG oxygenases evaluated. We obtained crystal structures of Desidustat and Enarodustat in complex with the human 2OG oxygenase factor inhibiting hypoxia\u2010inducible factor\u2010\u03b1 (FIH), which, together with modelling studies, inform on the binding modes of Desidustat and Enarodustat to active site Fe(II) in 2OG oxygenases, including PHD1\u20133. The results will help in the design of selective inhibitors of both the PHDs and other 2OG oxygenases, which are of medicinal interest due to their involvement inter alia in metabolic regulation, epigenetic signalling, DNA\u2010damage repair, and agrochemical resistance.<\/jats:p>","DOI":"10.1002\/cmdc.202400504","type":"journal-article","created":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T04:25:31Z","timestamp":1726633531000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Crystallographic and Selectivity Studies on the Approved HIF Prolyl Hydroxylase Inhibitors Desidustat and Enarodustat"],"prefix":"10.1002","volume":"19","author":[{"given":"Thomas P.","family":"Corner","sequence":"first","affiliation":[{"name":"Chemistry Research Laboratory Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research University of Oxford  12 Mansfield Road Oxford OX1 3TA United Kingdom"},{"name":"Present Address: Department of Molecular, Cellular, and Developmental Biology Yale University  New Haven, Connecticut 06511 United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eidarus","family":"Salah","sequence":"additional","affiliation":[{"name":"Chemistry Research Laboratory Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research University of Oxford  12 Mansfield Road Oxford OX1 3TA United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Tumber","sequence":"additional","affiliation":[{"name":"Chemistry Research Laboratory Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research University of Oxford  12 Mansfield Road Oxford OX1 3TA United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samanpreet","family":"Kaur","sequence":"additional","affiliation":[{"name":"Chemistry Research Laboratory Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research University of Oxford  12 Mansfield Road Oxford OX1 3TA United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Nakashima","sequence":"additional","affiliation":[{"name":"Institute of Natural Medicine University of Toyama  2630-Sugitani Toyama 930\u20130194 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark D.","family":"Allen","sequence":"additional","affiliation":[{"name":"Chemistry Research Laboratory Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research University of Oxford  12 Mansfield Road Oxford OX1 3TA United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara I.","family":"Schnaubelt","sequence":"additional","affiliation":[{"name":"Chemistry Research Laboratory Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research University of Oxford  12 Mansfield Road Oxford OX1 3TA United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Fiorini","sequence":"additional","affiliation":[{"name":"Chemistry Research Laboratory Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research University of Oxford  12 Mansfield Road Oxford OX1 3TA United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9465-777X","authenticated-orcid":false,"given":"Lennart","family":"Brewitz","sequence":"additional","affiliation":[{"name":"Chemistry Research Laboratory Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research University of Oxford  12 Mansfield Road Oxford OX1 3TA United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0290-6565","authenticated-orcid":false,"given":"Christopher J.","family":"Schofield","sequence":"additional","affiliation":[{"name":"Chemistry Research Laboratory Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research University of Oxford  12 Mansfield Road Oxford OX1 3TA United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,11,8]]},"reference":[{"key":"e_1_2_9_1_1","unstructured":"\u00a0"},{"key":"e_1_2_9_2_2","first-page":"671","volume":"75","author":"Killip S.","year":"2007","journal-title":"Am. Fam. Physician"},{"key":"e_1_2_9_3_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2021.642296"},{"key":"e_1_2_9_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/91.19.1616"},{"key":"e_1_2_9_5_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genom-083117-021320"},{"key":"e_1_2_9_6_1","first-page":"449","volume":"93","author":"Caro J.","year":"1979","journal-title":"J. Lab. Clin. Med."},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2019.04.022"},{"key":"e_1_2_9_8_1","first-page":"195","volume":"2","author":"Hayat A.","year":"2008","journal-title":"Patient Prefer. Adherence"},{"key":"e_1_2_9_9_1","unstructured":"\u00a0"},{"key":"e_1_2_9_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2362.2005.01525.x"},{"key":"e_1_2_9_11_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-02-270322"},{"key":"e_1_2_9_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.12.12.5447"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.12.5510"},{"key":"e_1_2_9_14_1","unstructured":"\u00a0"},{"key":"e_1_2_9_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg392"},{"key":"e_1_2_9_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00507-4"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M304982200"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature00767"},{"key":"e_1_2_9_19_1","unstructured":"\u00a0"},{"key":"e_1_2_9_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.749291"},{"key":"e_1_2_9_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1366"},{"key":"e_1_2_9_22_1","unstructured":"\u00a0"},{"key":"e_1_2_9_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2015.193"},{"key":"e_1_2_9_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.kisu.2020.12.002"},{"key":"e_1_2_9_25_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b01686"},{"key":"e_1_2_9_26_2","doi-asserted-by":"publisher","DOI":"10.1039\/c0cs00203h"},{"key":"e_1_2_9_27_1","unstructured":"\u00a0"},{"key":"e_1_2_9_28_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0132004"},{"key":"e_1_2_9_29_2","doi-asserted-by":"publisher","DOI":"10.1159\/000492181"},{"key":"e_1_2_9_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2018.04.039"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.3109\/15376516.2012.673088"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-024-00761-w"},{"key":"e_1_2_9_33_1","unstructured":"\u00a0"},{"key":"e_1_2_9_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-894X(03)00539-0"},{"key":"e_1_2_9_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phytochem.2015.06.028"},{"key":"e_1_2_9_36_2","doi-asserted-by":"publisher","DOI":"10.1080\/15592294.2020.1786305"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1039\/c3sc51122g"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12673"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2015.12.017"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2016.07.019"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.117.242503"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.7b00404"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1159\/000500232"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201700783"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1039\/C7SC02103H"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.122.001126"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.202100133"},{"key":"e_1_2_9_48_1","unstructured":"\u00a0"},{"key":"e_1_2_9_49_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.991402"},{"key":"e_1_2_9_50_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C200273200"},{"key":"e_1_2_9_51_1","unstructured":"\u00a0"},{"key":"e_1_2_9_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.02.020"},{"key":"e_1_2_9_53_2","doi-asserted-by":"publisher","DOI":"10.1039\/D3SC04253G"},{"key":"e_1_2_9_54_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202410438"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M704102200"},{"key":"e_1_2_9_56_1","unstructured":"\u00a0"},{"key":"e_1_2_9_57_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2011.08022.x"},{"key":"e_1_2_9_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42004-020-0290-5"},{"key":"e_1_2_9_59_1","unstructured":"\u00a0"},{"key":"e_1_2_9_60_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja050841b"},{"key":"e_1_2_9_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26673-2"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2004.069757"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1021\/ml100198y"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0601283103"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C200644200"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201208046"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.202614999"},{"key":"e_1_2_9_68_1","unstructured":"\u00a0"},{"key":"e_1_2_9_69_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1996.0897"},{"key":"e_1_2_9_70_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.10465"},{"key":"e_1_2_9_71_1","unstructured":"\u00a0"},{"key":"e_1_2_9_72_2","doi-asserted-by":"publisher","DOI":"10.1039\/D2CB00249C"},{"key":"e_1_2_9_73_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-65123-9"},{"key":"e_1_2_9_74_1","unstructured":"\u00a0"},{"key":"e_1_2_9_75_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-061516-044724"},{"key":"e_1_2_9_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2015.05.026"},{"key":"e_1_2_9_77_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2010.08.006"},{"key":"e_1_2_9_78_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201900557"},{"key":"e_1_2_9_79_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00605"},{"key":"e_1_2_9_80_1","doi-asserted-by":"publisher","DOI":"10.1177\/1087057111416660"},{"key":"e_1_2_9_81_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201810179"},{"key":"e_1_2_9_82_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm300677j"},{"key":"e_1_2_9_83_1","unstructured":"\u00a0"},{"key":"e_1_2_9_84_2","doi-asserted-by":"publisher","DOI":"10.1159\/000523949"},{"key":"e_1_2_9_85_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.119.258731"},{"key":"e_1_2_9_86_2","doi-asserted-by":"publisher","DOI":"10.1159\/000517053"},{"key":"e_1_2_9_87_2","doi-asserted-by":"publisher","DOI":"10.1111\/1744-9987.13724"},{"key":"e_1_2_9_88_1","unstructured":"\u00a0"},{"key":"e_1_2_9_89_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27275"},{"key":"e_1_2_9_90_2","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.202000147"},{"key":"e_1_2_9_91_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2020.115675"},{"key":"e_1_2_9_92_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jfluchem.2021.109804"},{"key":"e_1_2_9_93_2","doi-asserted-by":"publisher","DOI":"10.1039\/D0SC04301J"},{"key":"e_1_2_9_94_1","unstructured":"\u00a0"},{"key":"e_1_2_9_95_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118918"},{"key":"e_1_2_9_96_2","first-page":"1261","volume":"60","author":"Ince N.","year":"2000","journal-title":"Cancer Res."},{"key":"e_1_2_9_97_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-020-01669-w"},{"key":"e_1_2_9_98_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12711-7"},{"key":"e_1_2_9_99_1","unstructured":"\u00a0"},{"key":"e_1_2_9_100_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2010.09.016"},{"key":"e_1_2_9_101_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm401603e"},{"key":"e_1_2_9_102_1","unstructured":"\u00a0"},{"key":"e_1_2_9_103_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c01114"},{"key":"e_1_2_9_104_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c01204"},{"key":"e_1_2_9_105_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2008.10.054"},{"key":"e_1_2_9_106_1","unstructured":"R.\u2005C. Desai R. Sharma V. Pandya K. Shah S. Patel R. Chauhan R. Nair V. Joshi M. Patel M. Shukla (Cadila Healthcare Ltd.) US20190359574 A1 2019."},{"key":"e_1_2_9_107_1","unstructured":"R. Desai C.\u2005V. Pandya P.\u2005R. Patel (Cadila Healthcare Ltd.) WO2014102818 A1 2014.."},{"key":"e_1_2_9_108_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2009.06.002"},{"key":"e_1_2_9_109_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.012202"},{"key":"e_1_2_9_110_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05971"},{"key":"e_1_2_9_111_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0021889809045701"},{"key":"e_1_2_9_112_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0021889807021206"},{"key":"e_1_2_9_113_1","first-page":"861","volume":"75","author":"Liebschner D.","year":"2019","journal-title":"Acta Crystallogr."},{"key":"e_1_2_9_114_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444904019158"},{"key":"e_1_2_9_115_1","unstructured":"W.\u2005L. DeLano The PyMOL Molecular Graphics System De Lano Scientific San Carlos 2002."},{"key":"e_1_2_9_116_1","first-page":"148","volume":"73","author":"Liebschner D.","year":"2017","journal-title":"Acta Crystallogr."},{"key":"e_1_2_9_117_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/28.1.235"},{"key":"e_1_2_9_118_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1998.2401"},{"key":"e_1_2_9_119_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444909042073"},{"key":"e_1_2_9_120_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct200133y"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.202400504","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T17:05:11Z","timestamp":1760288711000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.202400504"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,8]]},"references-count":120,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2024,12,16]]}},"alternative-id":["10.1002\/cmdc.202400504"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.202400504","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,8]]},"assertion":[{"value":"2024-07-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202400504"}}