{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T13:22:57Z","timestamp":1777555377327,"version":"3.51.4"},"reference-count":45,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2022,10,1]],"date-time":"2022-10-01T00:00:00Z","timestamp":1664582400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2022,10,1]],"date-time":"2022-10-01T00:00:00Z","timestamp":1664582400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2023,9,9]],"date-time":"2023-09-09T00:00:00Z","timestamp":1694217600000},"content-version":"am","delay-in-days":343,"URL":"http:\/\/www.elsevier.com\/open-access\/userlicense\/1.0\/"},{"start":{"date-parts":[[2022,10,1]],"date-time":"2022-10-01T00:00:00Z","timestamp":1664582400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2022,10,1]],"date-time":"2022-10-01T00:00:00Z","timestamp":1664582400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2022,10,1]],"date-time":"2022-10-01T00:00:00Z","timestamp":1664582400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2022,10,1]],"date-time":"2022-10-01T00:00:00Z","timestamp":1664582400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2022,10,1]],"date-time":"2022-10-01T00:00:00Z","timestamp":1664582400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI103947"],"award-info":[{"award-number":["R01AI103947"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004167","name":"Medicines for Malaria Venture","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004167","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000928","name":"Welch Foundation","doi-asserted-by":"publisher","award":["I-1257"],"award-info":[{"award-number":["I-1257"]}],"id":[{"id":"10.13039\/100000928","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Biochemical Pharmacology"],"published-print":{"date-parts":[[2022,10]]},"DOI":"10.1016\/j.bcp.2022.115237","type":"journal-article","created":{"date-parts":[[2022,8,31]],"date-time":"2022-08-31T03:04:03Z","timestamp":1661915043000},"page":"115237","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":2,"special_numbering":"C","title":["Development of a biomarker to monitor target engagement after treatment with dihydroorotate dehydrogenase inhibitors"],"prefix":"10.1016","volume":"204","author":[{"given":"Michael A.","family":"Pontikos","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"Leija","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiyu","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Kilgore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Belen","family":"Tornesi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"Adenmatten","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margaret A.","family":"Phillips","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noelle S.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1016\/j.bcp.2022.115237_b0005","unstructured":"World Health Organization, World Malaria Report, 2020. (Accessed dec 15 2020)."},{"key":"10.1016\/j.bcp.2022.115237_b0010","doi-asserted-by":"crossref","first-page":"17050","DOI":"10.1038\/nrdp.2017.50","article-title":"Malaria","volume":"3","author":"Phillips","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"10.1016\/j.bcp.2022.115237_b0015","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1146\/annurev.micro.091208.073424","article-title":"Mitochondrial evolution and functions in malaria parasites","volume":"63","author":"Vaidya","year":"2009","journal-title":"Annu Rev Microbiol"},{"issue":"3","key":"10.1016\/j.bcp.2022.115237_b0020","doi-asserted-by":"crossref","first-page":"226","DOI":"10.2174\/187152610791163336","article-title":"Plasmodium dihydroorotate dehydrogenase: a promising target for novel anti-malarial chemotherapy","volume":"10","author":"Phillips","year":"2010","journal-title":"Infect Disord Drug Targets"},{"issue":"8","key":"10.1016\/j.bcp.2022.115237_b0025","doi-asserted-by":"crossref","first-page":"3148","DOI":"10.1021\/jm301848w","article-title":"On dihydroorotate dehydrogenases and their inhibitors and uses","volume":"56","author":"Munier-Lehmann","year":"2013","journal-title":"J Med Chem"},{"issue":"5","key":"10.1016\/j.bcp.2022.115237_b0030","doi-asserted-by":"crossref","first-page":"2067","DOI":"10.1042\/BST20200224","article-title":"Driving antimalarial design through understanding of target mechanism","volume":"48","author":"Calic","year":"2020","journal-title":"Biochem Soc Trans"},{"issue":"6","key":"10.1016\/j.bcp.2022.115237_b0035","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.pt.2021.01.009","article-title":"Malaria Drug Accelerator, MalDA, Accelerating Malaria Drug Discovery","volume":"37","author":"Yang","year":"2021","journal-title":"Trends Parasitol"},{"issue":"15","key":"10.1016\/j.bcp.2022.115237_b0040","doi-asserted-by":"crossref","first-page":"5540","DOI":"10.1021\/jm200592f","article-title":"Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential","volume":"54","author":"Coteron","year":"2011","journal-title":"J Med Chem"},{"issue":"296","key":"10.1016\/j.bcp.2022.115237_b0045","doi-asserted-by":"crossref","first-page":"296ra111","DOI":"10.1126\/scitranslmed.aaa6645","article-title":"A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria","volume":"7","author":"Phillips","year":"2015","journal-title":"Sci Transl Med"},{"issue":"9","key":"10.1016\/j.bcp.2022.115237_b0050","doi-asserted-by":"crossref","first-page":"4929","DOI":"10.1021\/acs.jmedchem.0c00311","article-title":"Lead Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series for the Treatment of Malaria","volume":"63","author":"Kokkonda","year":"2020","journal-title":"J Med Chem"},{"issue":"9","key":"10.1016\/j.bcp.2022.115237_b0055","doi-asserted-by":"crossref","first-page":"6085","DOI":"10.1021\/acs.jmedchem.1c00173","article-title":"Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series","volume":"64","author":"Palmer","year":"2021","journal-title":"J Med Chem"},{"issue":"1","key":"10.1016\/j.bcp.2022.115237_b0060","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.01371-19","article-title":"A Single-Dose Combination Study with the Experimental Antimalarials Artefenomel and DSM265 To Determine Safety and Antimalarial Activity against Blood-Stage Plasmodium falciparum in Healthy Volunteers","volume":"64","author":"McCarthy","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"issue":"4","key":"10.1016\/j.bcp.2022.115237_b0065","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.01837-18","article-title":"DSM265 at 400 Milligrams Clears Asexual Stage Parasites but Not Mature Gametocytes from the Blood of Healthy Subjects Experimentally Infected with Plasmodium falciparum","volume":"63","author":"Collins","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"issue":"8","key":"10.1016\/j.bcp.2022.115237_b0070","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1016\/S1473-3099(18)30309-8","article-title":"Antimalarial activity of single-dose DSM265, a novel plasmodium dihydroorotate dehydrogenase inhibitor, in patients with uncomplicated Plasmodium falciparum or Plasmodium vivax malaria infection: a proof-of-concept, open-label, phase 2a study","volume":"18","author":"Llanos-Cuentas","year":"2018","journal-title":"Lancet Infect Dis"},{"issue":"5","key":"10.1016\/j.bcp.2022.115237_b0075","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1093\/infdis\/jix613","article-title":"A Randomized Trial Evaluating the Prophylactic Activity of DSM265 Against Preerythrocytic Plasmodium falciparum Infection During Controlled Human Malarial Infection by Mosquito Bites and Direct Venous Inoculation","volume":"217","author":"Murphy","year":"2018","journal-title":"J Infect Dis"},{"issue":"6","key":"10.1016\/j.bcp.2022.115237_b0080","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/S1473-3099(17)30139-1","article-title":"DSM265 for Plasmodium falciparum chemoprophylaxis: a randomised, double blinded, phase 1 trial with controlled human malaria infection","volume":"17","author":"Sulyok","year":"2017","journal-title":"Lancet Infect Dis"},{"issue":"6","key":"10.1016\/j.bcp.2022.115237_b0085","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/S1473-3099(17)30171-8","article-title":"Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a\/1b randomised study","volume":"17","author":"McCarthy","year":"2017","journal-title":"Lancet Infect Dis"},{"issue":"6","key":"10.1016\/j.bcp.2022.115237_b0090","doi-asserted-by":"crossref","first-page":"874","DOI":"10.2174\/1570159X14666161208151525","article-title":"From Leflunomide to Teriflunomide: Drug Development and Immunosuppressive Oral Drugs in the Treatment of Multiple Sclerosis","volume":"15","author":"Aly","year":"2017","journal-title":"Curr Neuropharmacol"},{"issue":"21","key":"10.1016\/j.bcp.2022.115237_b0095","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.1093\/ajhp\/55.21.2225","volume":"55","year":"1998","journal-title":"Am J Health Syst Pharm"},{"issue":"1","key":"10.1016\/j.bcp.2022.115237_b0100","first-page":"3","article-title":"Targeting of Hematologic Malignancies with PTC299","volume":"18","author":"Cao","year":"2019","journal-title":"A Novel Potent Inhibitor of Dihydroorotate Dehydrogenase with Favorable Pharmaceutical Properties, Mol Cancer Ther"},{"issue":"10","key":"10.1016\/j.bcp.2022.115237_b0105","doi-asserted-by":"crossref","first-page":"2403","DOI":"10.1038\/s41375-019-0461-5","article-title":"The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies","volume":"33","author":"Christian","year":"2019","journal-title":"Leukemia"},{"issue":"10","key":"10.1016\/j.bcp.2022.115237_b0110","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1007\/s13238-020-00768-w","article-title":"Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2","volume":"11","author":"Xiong","year":"2020","journal-title":"Protein Cell"},{"key":"10.1016\/j.bcp.2022.115237_b0115","doi-asserted-by":"crossref","DOI":"10.1016\/j.virusres.2020.198246","article-title":"The DHODH inhibitor PTC299 arrests SARS-CoV-2 replication and suppresses induction of inflammatory cytokines","volume":"292","author":"Luban","year":"2021","journal-title":"Virus Res"},{"issue":"3","key":"10.1016\/j.bcp.2022.115237_b0120","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1083\/jcb.201107058","article-title":"Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export","volume":"196","author":"Zhang","year":"2012","journal-title":"J Cell Biol"},{"issue":"3","key":"10.1016\/j.bcp.2022.115237_b0125","article-title":"Review of the Novel Investigational Antifungal Olorofim","volume":"6","author":"Wiederhold","year":"2020","journal-title":"J Fungi (Basel)"},{"issue":"11","key":"10.1016\/j.bcp.2022.115237_b0130","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1373\/clinchem.2004.038869","article-title":"Analysis of pyrimidine synthesis \u201cde novo\u201d intermediates in urine and dried urine filter- paper strips with HPLC-electrospray tandem mass spectrometry","volume":"50","author":"van Kuilenburg","year":"2004","journal-title":"Clin Chem"},{"key":"10.1016\/j.bcp.2022.115237_b0135","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.jchromb.2013.05.001","article-title":"Collection and determination of nucleotide metabolites in neonatal and adult saliva by high performance liquid chromatography with tandem mass spectrometry","volume":"931","author":"Al-Shehri","year":"2013","journal-title":"J Chromatogr B Analyt Technol Biomed Life Sci"},{"issue":"1\u20132","key":"10.1016\/j.bcp.2022.115237_b0140","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.ymgme.2016.06.008","article-title":"Elevated plasma dihydroorotate in Miller syndrome: Biochemical, diagnostic and clinical implications, and treatment with uridine","volume":"119","author":"Duley","year":"2016","journal-title":"Mol Genet Metab"},{"issue":"11","key":"10.1016\/j.bcp.2022.115237_b0145","doi-asserted-by":"crossref","first-page":"6635","DOI":"10.1128\/AAC.01224-16","article-title":"Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways","volume":"60","author":"Allman","year":"2016","journal-title":"Antimicrob Agents Chemother"},{"issue":"8","key":"10.1016\/j.bcp.2022.115237_b0150","doi-asserted-by":"crossref","first-page":"2627","DOI":"10.1002\/jps.24506","article-title":"Plasma Protein Binding of Challenging Compounds","volume":"104","author":"Riccardi","year":"2015","journal-title":"J Pharm Sci"},{"issue":"2","key":"10.1016\/j.bcp.2022.115237_b0155","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1002\/rcm.1777","article-title":"A novel liquid chromatography\/tandem mass spectrometry based depletion method for measuring red blood cell partitioning of pharmaceutical compounds in drug discovery","volume":"19","author":"Yu","year":"2005","journal-title":"Rapid Commun Mass Spectrom"},{"issue":"10","key":"10.1016\/j.bcp.2022.115237_b0160","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1124\/dmd.31.10.1240","article-title":"In vitro metabolism studies on the isoxazole ring scission in the anti-inflammatory agent lefluonomide to its active alpha-cyanoenol metabolite A771726: mechanistic similarities with the cytochrome P450-catalyzed dehydration of aldoximes","volume":"31","author":"Kalgutkar","year":"2003","journal-title":"Drug Metab Dispos"},{"issue":"2","key":"10.1016\/j.bcp.2022.115237_b0165","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.jpba.2011.01.034","article-title":"Quantitation of total and free teriflunomide (A77 1726) in human plasma by LC-MS\/MS","volume":"55","author":"Rakhila","year":"2011","journal-title":"J Pharm Biomed Anal"},{"issue":"3","key":"10.1016\/j.bcp.2022.115237_b0170","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.molcel.2014.09.025","article-title":"Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport","volume":"56","author":"Yang","year":"2014","journal-title":"Mol Cell"},{"issue":"1","key":"10.1016\/j.bcp.2022.115237_b0175","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0016286","article-title":"The development of metabolomic sampling procedures for Pichia pastoris, and baseline metabolome data","volume":"6","author":"Tredwell","year":"2011","journal-title":"PLoS One"},{"issue":"3","key":"10.1016\/j.bcp.2022.115237_b0180","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1177\/1469066720918446","article-title":"Data normalization strategies in metabolomics: Current challenges, approaches, and tools","volume":"26","author":"Misra","year":"2020","journal-title":"Eur J Mass Spectrom (Chichester)"},{"issue":"4","key":"10.1016\/j.bcp.2022.115237_b0185","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1021\/bi952168g","article-title":"The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase","volume":"35","author":"Davis","year":"1996","journal-title":"Biochemistry"},{"issue":"2","key":"10.1016\/j.bcp.2022.115237_b0190","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1093\/toxsci\/kfp022","article-title":"Inhibiting the teratogenicity of the immunosuppressant leflunomide in mice by supplementation of exogenous uridine","volume":"108","author":"Fukushima","year":"2009","journal-title":"Toxicol Sci"},{"issue":"1","key":"10.1016\/j.bcp.2022.115237_b0195","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.reprotox.2009.09.001","article-title":"Microarray analysis of Leflunomide-induced limb malformations in CD-1 mice","volume":"29","author":"Fukushima","year":"2010","journal-title":"Reprod Toxicol"},{"issue":"1","key":"10.1016\/j.bcp.2022.115237_b0200","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1530\/JOE-17-0536","article-title":"Control of hyperglycemia in male mice by leflunomide: mechanisms of action","volume":"237","author":"Chen","year":"2018","journal-title":"J Endocrinol"},{"issue":"3\u20134","key":"10.1016\/j.bcp.2022.115237_b0205","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.reprotox.2007.05.006","article-title":"Teratogenicity study of the dihydroorotate-dehydrogenase inhibitor and protein tyrosine kinase inhibitor Leflunomide in mice","volume":"24","author":"Fukushima","year":"2007","journal-title":"Reprod Toxicol"},{"key":"10.1016\/j.bcp.2022.115237_b0210","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2019.111681","article-title":"Dihydroorotate dehydrogenase inhibitors in anti-infective drug research","volume":"183","author":"Boschi","year":"2019","journal-title":"Eur J Med Chem"},{"issue":"1","key":"10.1016\/j.bcp.2022.115237_b0215","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/S1056-8719(00)00110-6","article-title":"Present and future in vitro approaches for drug metabolism","volume":"44","author":"Ekins","year":"2000","journal-title":"J Pharmacol Toxicol Methods"},{"issue":"2","key":"10.1016\/j.bcp.2022.115237_b0220","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.reprotox.2012.05.003","article-title":"Biomarkers of teratogenesis: suggestions from animal studies","volume":"34","author":"Giavini","year":"2012","journal-title":"Reprod Toxicol"},{"key":"10.1016\/j.bcp.2022.115237_b0225","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.jpba.2016.06.017","article-title":"Quantitative analysis of endogenous compounds","volume":"128","author":"Thakare","year":"2016","journal-title":"J Pharm Biomed Anal"}],"container-title":["Biochemical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0006295222003318?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0006295222003318?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T18:10:01Z","timestamp":1777399801000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0006295222003318"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10]]},"references-count":45,"alternative-id":["S0006295222003318"],"URL":"https:\/\/doi.org\/10.1016\/j.bcp.2022.115237","relation":{},"ISSN":["0006-2952"],"issn-type":[{"value":"0006-2952","type":"print"}],"subject":[],"published":{"date-parts":[[2022,10]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Development of a biomarker to monitor target engagement after treatment with dihydroorotate dehydrogenase inhibitors","name":"articletitle","label":"Article Title"},{"value":"Biochemical Pharmacology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.bcp.2022.115237","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2022 Elsevier Inc. All rights reserved.","name":"copyright","label":"Copyright"}],"article-number":"115237"}}