{"entity": "researcher", "timestamp": "2026-07-13T09:23:26.325Z", "family": "Knapp", "given": "Stefan", "initials": "S", "orcid": "0000-0001-5995-6494", "affiliations": ["Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Frankfurt, Germany."], "links": {"self": {"href": "https://publications.scilifelab.se/researcher/c4d84c40612d48f280d4ead25558d835.json"}, "display": {"href": "https://publications.scilifelab.se/researcher/c4d84c40612d48f280d4ead25558d835"}}, "publications": [{"entity": "publication", "iuid": "ea1d7c59296941b4bb2c44e61fe0cac6", "links": {"self": {"href": "https://publications.scilifelab.se/publication/ea1d7c59296941b4bb2c44e61fe0cac6.json"}, "display": {"href": "https://publications.scilifelab.se/publication/ea1d7c59296941b4bb2c44e61fe0cac6"}}, "title": "Nucleobase catalysts for the enzymatic activation of 8-oxoguanine DNA glycosylase 1.", "authors": [{"family": "Hank", "given": "Emily C", "initials": "EC", "orcid": "0000-0002-3777-4697", "researcher": {"href": "https://publications.scilifelab.se/researcher/b3e38aa74d2c4ae0b7c77d7f1da17727.json"}}, {"family": "D'Arcy-Evans", "given": "Nicholas D", "initials": "ND"}, {"family": "Scaletti", "given": "Emma Rose", "initials": "ER"}, {"family": "Ben\u00edtez-Buelga", "given": "Carlos", "initials": "C"}, {"family": "Wallner", "given": "Olov", "initials": "O", "orcid": "0000-0002-6481-237X", "researcher": {"href": "https://publications.scilifelab.se/researcher/83eb2f7ee2f34f2cbacaae2dadcd90e9.json"}}, {"family": "Ortis", "given": "Florian", "initials": "F"}, {"family": "Zhou", "given": "Kaixin", "initials": "K"}, {"family": "Meng", "given": "Liuzhen", "initials": "L"}, {"family": "Del Prado", "given": "Alicia", "initials": "A", "orcid": "0000-0002-5480-0367", "researcher": {"href": "https://publications.scilifelab.se/researcher/39389cbfdeac46e8985c1597e00d45e1.json"}}, {"family": "Calvo", "given": "Patricia", "initials": "P"}, {"family": "Alml\u00f6f", "given": "Ingrid", "initials": "I"}, {"family": "Wiita", "given": "Elis\u00e9e", "initials": "E"}, {"family": "Nierlin", "given": "Karen", "initials": "K"}, {"family": "Ko\u0161enina", "given": "Sara", "initials": "S", "orcid": "0000-0001-7893-0249", "researcher": {"href": "https://publications.scilifelab.se/researcher/9370d4ecf19c438bb205c43c23f94f26.json"}}, {"family": "Kr\u00e4mer", "given": "Andreas", "initials": "A"}, {"family": "Eddershaw", "given": "Alice", "initials": "A"}, {"family": "Kehler", "given": "Mario", "initials": "M"}, {"family": "Long", "given": "Maeve", "initials": "M", "orcid": "0000-0001-5146-0750", "researcher": {"href": "https://publications.scilifelab.se/researcher/b68df86f81504376b77b98b0916c84c4.json"}}, {"family": "Jemth", "given": "Ann-Sofie", "initials": "AS", "orcid": "0000-0002-7550-1833", "researcher": {"href": "https://publications.scilifelab.se/researcher/fd07c6c543544af1a904e039f73ba857.json"}}, {"family": "Dawson", "given": "Holly", "initials": "H"}, {"family": "Stewart", "given": "Josephine", "initials": "J", "orcid": "0000-0002-3506-5264", "researcher": {"href": "https://publications.scilifelab.se/researcher/62e8f2e54f1a4f1d96d8f4ae1de97a93.json"}}, {"family": "Dickey", "given": "Adam", "initials": "A"}, {"family": "Astorga", "given": "Mikhael E", "initials": "ME"}, {"family": "Varga", "given": "Marek", "initials": "M"}, {"family": "Homan", "given": "Evert J", "initials": "EJ", "orcid": "0000-0002-9057-1848", "researcher": {"href": "https://publications.scilifelab.se/researcher/f0d6d2714b2544bfa37d383ef1357ba4.json"}}, {"family": "Scobie", "given": "Martin", "initials": "M", "orcid": "0000-0002-7073-8495", "researcher": {"href": "https://publications.scilifelab.se/researcher/87c041a8b3414f5db02873dc8013806b.json"}}, {"family": "Knapp", "given": "Stefan", "initials": "S", "orcid": "0000-0001-5995-6494", "researcher": {"href": "https://publications.scilifelab.se/researcher/c4d84c40612d48f280d4ead25558d835.json"}}, {"family": "Sastre", "given": "Leandro", "initials": "L"}, {"family": "Stenmark", "given": "P\u00e5l", "initials": "P", "orcid": "0000-0003-4777-3417", "researcher": {"href": "https://publications.scilifelab.se/researcher/d97eba9f5edf4d76a5259c4baa8366c5.json"}}, {"family": "de Vega", "given": "Miguel", "initials": "M", "orcid": "0000-0003-1285-7549", "researcher": {"href": "https://publications.scilifelab.se/researcher/77e5f3b41f634728b525ff94b0496bc4.json"}}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications.scilifelab.se/researcher/3d7256c271ea4adea404d4ff355f804e.json"}}, {"family": "Michel", "given": "Maurice", "initials": "M", "orcid": "0000-0003-3261-2493", "researcher": {"href": "https://publications.scilifelab.se/researcher/4f7cb5d695254481b745f86a824ac1b5.json"}}], "type": "journal article", "published": "2025-10-28", "journal": {"title": "RSC Chem Biol", "issn": "2633-0679", "issn-l": null}, "abstract": "Bifunctional DNA glycosylases employ an active site lysine or the N-terminus to form a Schiff base with an abasic (AP) site base excision repair intermediate. For 8-oxoguanine DNA glycosylase 1 (OGG1), cleaving this reversible structure is the rate-determining step in the initiation of 8-oxoguanine (8-oxoG) repair in DNA. Evolution has led OGG1 to use a product-assisted catalysis approach, where the excised 8-oxoG acts as a Br\u00f8nsted base for cleavage of a Schiff base intermediate. However, the physicochemical properties of 8-oxoG significantly limit the inherent enzymatic turnover leading to a weak, cellularly absent, AP lyase activity. We hypothesized that chemical synthesis of purine analogues enables access to complex structures that are suitable as product-like catalysts. Herein, the nucleobase landscape is profiled for its potential to increase OGG1 Schiff base cleavage. 8-Substituted 6-thioguanines emerge as potent and selective scaffolds enabling OGG1 to cleave AP sites opposite any canonical nucleobase by \u03b2-elimination. This effectively broadens the enzymatic substrate scope of OGG1, shaping a complete, artificial AP-lyase function. In addition, a second class of compounds, 6-substituted pyrazolo-[3,4-d]-pyrimidines, stimulate OGG1 function at high pH, while thioguanines govern enzymatic control at acidic pH. This enables up to 20-fold increased enzyme turnover and a de novo OGG1 \u03b2-elimination in conditions commonly not tolerated. The tool compounds employed here are non-toxic in cells and stimulate the repair of AP sites through a natural, APE1 dependent pathway, as opposed to previously reported \u03b2,\u03b4-lyase stimulator TH10785.", "doi": "10.1039/d4cb00323c", "pmid": "41195166", "labels": {"Chemical Biology Consortium Sweden": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC12584757"}, {"db": "pii", "key": "d4cb00323c"}], "notes": [], "created": "2025-11-25T11:35:44.104Z", "modified": "2025-11-27T13:32:01.339Z"}, {"entity": "publication", "iuid": "d6b6473e8ba241aba65ecf65773c1ac4", "links": {"self": {"href": "https://publications.scilifelab.se/publication/d6b6473e8ba241aba65ecf65773c1ac4.json"}, "display": {"href": "https://publications.scilifelab.se/publication/d6b6473e8ba241aba65ecf65773c1ac4"}}, "title": "Toward target 2035: EUbOPEN - a public-private partnership to enable & unlock biology in the open.", "authors": [{"family": "Tredup", "given": "Claudia", "initials": "C", "orcid": "0000-0001-6518-3344", "researcher": {"href": "https://publications.scilifelab.se/researcher/f9598692f92a42cbbac352bda93085c8.json"}}, {"family": "Ackloo", "given": "Suzanne", "initials": "S", "orcid": "0000-0002-9696-1839", "researcher": {"href": "https://publications.scilifelab.se/researcher/95141c024a414c3aaa53daf781433e87.json"}}, {"family": "Beck", "given": "Hartmut", "initials": "H"}, {"family": "Brown", "given": "Peter J", "initials": "PJ"}, {"family": "Bullock", "given": "Alex N", "initials": "AN", "orcid": "0000-0001-6757-0436", "researcher": {"href": "https://publications.scilifelab.se/researcher/68163f1d336e4ad4818d6b2cdbfeaf0e.json"}}, {"family": "Ciulli", "given": "Alessio", "initials": "A", "orcid": "0000-0002-8654-1670", "researcher": {"href": "https://publications.scilifelab.se/researcher/d36e64e6af894ca28c2d4592896b0ae0.json"}}, {"family": "Dikic", "given": "Ivan", "initials": "I", "orcid": "0000-0001-8156-9511", "researcher": {"href": "https://publications.scilifelab.se/researcher/d81061feaa3a49b4a4859566c7542e72.json"}}, {"family": "Edfeldt", "given": "Kristina", "initials": "K", "orcid": "0000-0002-0550-1133", "researcher": {"href": "https://publications.scilifelab.se/researcher/bf9c3d4af5dd4a538513a6648486f5eb.json"}}, {"family": "Edwards", "given": "Aled M", "initials": "AM"}, {"family": "Elkins", "given": "Jonathan M", "initials": "JM"}, {"family": "Farin", "given": "Henner F", "initials": "HF", "orcid": "0000-0003-1558-5366", "researcher": {"href": "https://publications.scilifelab.se/researcher/7301a4e75e33404cb68b91154af0075f.json"}}, {"family": "Fon", "given": "Edward A", "initials": "EA", "orcid": "0000-0002-5520-6239", "researcher": {"href": "https://publications.scilifelab.se/researcher/503836b6aa764c888988ce730a9386f2.json"}}, {"family": "Gstaiger", "given": "Matthias", "initials": "M"}, {"family": "G\u00fcnther", "given": "Judith", "initials": "J"}, {"family": "Gustavsson", "given": "Anna-Lena", "initials": "AL"}, {"family": "H\u00e4berle", "given": "Sandra", "initials": "S"}, {"family": "Isigkeit", "given": "Laura", "initials": "L", "orcid": "0000-0002-0168-1093", "researcher": {"href": "https://publications.scilifelab.se/researcher/a14d651c3033499f8e72e47860413968.json"}}, {"family": "Huber", "given": "Kilian V M", "initials": "KVM", "orcid": "0000-0002-1103-5300", "researcher": {"href": "https://publications.scilifelab.se/researcher/8386d4f361df45ee863e5fca46eb875b.json"}}, {"family": "Kotschy", "given": "Andras", "initials": "A", "orcid": "0000-0002-7675-3864", "researcher": {"href": "https://publications.scilifelab.se/researcher/9853686b9acb4d86898a872b10bfdfc9.json"}}, {"family": "Kr\u00e4mer", "given": "Oliver", "initials": "O"}, {"family": "Leach", "given": "Andrew R", "initials": "AR"}, {"family": "Marsden", "given": "Brian D", "initials": "BD"}, {"family": "Matsui", "given": "Hisanori", "initials": "H"}, {"family": "Merk", "given": "Daniel", "initials": "D", "orcid": "0000-0002-5359-8128", "researcher": {"href": "https://publications.scilifelab.se/researcher/b3adffe811c743bda016dfe7d25c8bec.json"}}, {"family": "Montel", "given": "Florian", "initials": "F"}, {"family": "Mulder", "given": "Monique P C", "initials": "MPC", "orcid": "0000-0001-5386-7132", "researcher": {"href": "https://publications.scilifelab.se/researcher/0f56d7418ec94a44a274fe83b5586f8d.json"}}, {"family": "M\u00fcller", "given": "Susanne", "initials": "S", "orcid": "0000-0003-2402-4157", "researcher": {"href": "https://publications.scilifelab.se/researcher/addee378115f41cba3e59d223e8276df.json"}}, {"family": "Owen", "given": "Dafydd R", "initials": "DR", "orcid": "0000-0003-3106-7809", "researcher": {"href": "https://publications.scilifelab.se/researcher/fc3e57270832497f8996b1cd583031d6.json"}}, {"family": "Proschak", "given": "Ewgenij", "initials": "E"}, {"family": "R\u00f6hm", "given": "Sandra", "initials": "S"}, {"family": "Stolz", "given": "Alexandra", "initials": "A", "orcid": "0000-0002-3340-439X", "researcher": {"href": "https://publications.scilifelab.se/researcher/0b40ffdc8fcf497499fa4ba93a530b8d.json"}}, {"family": "Sundstr\u00f6m", "given": "Michael", "initials": "M"}, {"family": "von Delft", "given": "Frank", "initials": "F", "orcid": "0000-0003-0378-0017", "researcher": {"href": "https://publications.scilifelab.se/researcher/1c50d3e370c34cba9d9ce376273fd5fc.json"}}, {"family": "Willson", "given": "Timothy M", "initials": "TM"}, {"family": "Arrowsmith", "given": "Cheryl H", "initials": "CH"}, {"family": "Knapp", "given": "Stefan", "initials": "S", "orcid": "0000-0001-5995-6494", "researcher": {"href": "https://publications.scilifelab.se/researcher/c4d84c40612d48f280d4ead25558d835.json"}}], "type": "editorial", "published": "2025-02-19", "journal": {"title": "RSC Med Chem", "issn": "2632-8682", "issn-l": null, "volume": "16", "issue": "2", "pages": "457-464"}, "abstract": "Target 2035 is a global initiative that seeks to identify a pharmacological modulator of most human proteins by the year 2035. As part of an ongoing series of annual updates of this initiative, we summarise here the efforts of the EUbOPEN project whose objectives and results are making a strong contribution to the goals of Target 2035. EUbOPEN is a public-private partnership with four pillars of activity: (1) chemogenomic library collections, (2) chemical probe discovery and technology development for hit-to-lead chemistry, (3) profiling of bioactive compounds in patient-derived disease assays, and (4) collection, storage and dissemination of project-wide data and reagents. The substantial outputs of this programme include a chemogenomic compound library covering one third of the druggable proteome, as well as 100 chemical probes, both profiled in patient derived assays, as well as hundreds of data sets deposited in existing public data repositories and a project-specific data resource for exploring EUbOPEN outputs.", "doi": "10.1039/d4md00735b", "pmid": "39618964", "labels": {"Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [{"db": "pmc", "key": "PMC11605244"}, {"db": "pii", "key": "d4md00735b"}], "notes": [], "created": "2024-12-16T09:06:27.733Z", "modified": "2025-10-17T13:04:26.868Z"}, {"entity": "publication", "iuid": "483fd25be0c940a88ec33ee37fd176c8", "links": {"self": {"href": "https://publications.scilifelab.se/publication/483fd25be0c940a88ec33ee37fd176c8.json"}, "display": {"href": "https://publications.scilifelab.se/publication/483fd25be0c940a88ec33ee37fd176c8"}}, "title": "Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress.", "authors": [{"family": "Bonagas", "given": "Nadilly", "initials": "N", "orcid": "0000-0001-7336-4065", "researcher": {"href": "https://publications.scilifelab.se/researcher/1e38f3b0752740969c5c13fb77885b27.json"}}, {"family": "Gustafsson", "given": "Nina M S", "initials": "NMS"}, {"family": "Henriksson", "given": "Martin", "initials": "M"}, {"family": "Marttila", "given": "Petra", "initials": "P", "orcid": "0000-0002-0115-8067", "researcher": {"href": "https://publications.scilifelab.se/researcher/2e3e92bdf843456784f98d3b521d2ccd.json"}}, {"family": "Gustafsson", "given": "Robert", "initials": "R", "orcid": "0000-0002-4854-5531", "researcher": {"href": "https://publications.scilifelab.se/researcher/16dd7e73adad4f85972d1d546bfa6d2a.json"}}, {"family": "Wiita", "given": "Elis\u00e9e", "initials": "E"}, {"family": "Borhade", "given": "Sanjay", "initials": "S"}, {"family": "Green", "given": "Alanna C", "initials": "AC"}, {"family": "Vallin", "given": "Karl S A", "initials": "KSA"}, {"family": "Sarno", "given": "Antonio", "initials": "A"}, {"family": "Svensson", "given": "Richard", "initials": "R"}, {"family": "G\u00f6kt\u00fcrk", "given": "Camilla", "initials": "C"}, {"family": "Pham", "given": "Therese", "initials": "T"}, {"family": "Jemth", "given": "Ann-Sofie", "initials": "AS", "orcid": "0000-0002-7550-1833", "researcher": {"href": "https://publications.scilifelab.se/researcher/fd07c6c543544af1a904e039f73ba857.json"}}, {"family": "Loseva", "given": "Olga", "initials": "O"}, {"family": "Cookson", "given": "Victoria", "initials": "V", "orcid": "0000-0003-3089-4837", "researcher": {"href": "https://publications.scilifelab.se/researcher/3cd81b473de74c26bad811b3c2f25b7f.json"}}, {"family": "Kiweler", "given": "Nicole", "initials": "N", "orcid": "0000-0001-7493-703X", "researcher": {"href": "https://publications.scilifelab.se/researcher/f8b0eaee2d574b4daba1ee735c512797.json"}}, {"family": "Sandberg", "given": "Lars", "initials": "L"}, {"family": "Rasti", "given": "Azita", "initials": "A"}, {"family": "Unterlass", "given": "Judith E", "initials": "JE"}, {"family": "Haraldsson", "given": "Martin", "initials": "M"}, {"family": "Andersson", "given": "Yasmin", "initials": "Y"}, {"family": "Scaletti", "given": "Emma R", "initials": "ER"}, {"family": "Bengtsson", "given": "Christoffer", "initials": "C"}, {"family": "Paulin", "given": "Cynthia B J", "initials": "CBJ"}, {"family": "Sanjiv", "given": "Kumar", "initials": "K"}, {"family": "Abdurakhmanov", "given": "Eldar", "initials": "E"}, {"family": "Pudelko", "given": "Linda", "initials": "L"}, {"family": "Kunz", "given": "Ben", "initials": "B"}, {"family": "Desroses", "given": "Matthieu", "initials": "M"}, {"family": "Iliev", "given": "Petar", "initials": "P"}, {"family": "F\u00e4rneg\u00e5rdh", "given": "Katarina", "initials": "K"}, {"family": "Kr\u00e4mer", "given": "Andreas", "initials": "A", "orcid": "0000-0003-3294-2660", "researcher": {"href": "https://publications.scilifelab.se/researcher/37f158e9b24d43b69753ccbf029cb793.json"}}, {"family": "Garg", "given": "Neeraj", "initials": "N"}, {"family": "Michel", "given": "Maurice", "initials": "M"}, {"family": "H\u00e4ggblad", "given": "Sara", "initials": "S"}, {"family": "Jarvius", "given": "Malin", "initials": "M"}, {"family": "Kalder\u00e9n", "given": "Christina", "initials": "C"}, {"family": "Jensen", "given": "Amanda B\u00f6gedahl", "initials": "AB"}, {"family": "Alml\u00f6f", "given": "Ingrid", "initials": "I"}, {"family": "Karsten", "given": "Stella", "initials": "S", "orcid": "0000-0001-6191-4314", "researcher": {"href": "https://publications.scilifelab.se/researcher/4cbde9247c7145ff8ea0bbc0b0c5c477.json"}}, {"family": "Zhang", "given": "Si Min", "initials": "SM"}, {"family": "H\u00e4ggblad", "given": "Maria", "initials": "M"}, {"family": "Eriksson", "given": "Anders", "initials": "A"}, {"family": "Liu", "given": "Jianping", "initials": "J", "orcid": "0000-0002-7336-3895", "researcher": {"href": "https://publications.scilifelab.se/researcher/e77624d9d5b841608e142afbe2ead1d7.json"}}, {"family": "Glinghammar", "given": "Bj\u00f6rn", "initials": "B"}, {"family": "Nekhotiaeva", "given": "Natalia", "initials": "N"}, {"family": "Klingeg\u00e5rd", "given": "Fredrik", "initials": "F"}, {"family": "Koolmeister", "given": "Tobias", "initials": "T"}, {"family": "Martens", "given": "Ulf", "initials": "U"}, {"family": "Llona-Minguez", "given": "Sabin", "initials": "S"}, {"family": "Moulson", "given": "Ruth", "initials": "R"}, {"family": "Nordstr\u00f6m", "given": "Helena", "initials": "H"}, {"family": "Parrow", "given": "Vendela", "initials": "V"}, {"family": "Dahllund", "given": "Leif", "initials": "L"}, {"family": "Sj\u00f6berg", "given": "Birger", "initials": "B"}, {"family": "Vargas", "given": "Irene L", "initials": "IL"}, {"family": "Vo", "given": "Duy Duc", "initials": "DD"}, {"family": "Wannberg", "given": "Johan", "initials": "J", "orcid": "0000-0001-5494-0848", "researcher": {"href": "https://publications.scilifelab.se/researcher/d093f5fb52f644ce8994f3a6308272a8.json"}}, {"family": "Knapp", "given": "Stefan", "initials": "S", "orcid": "0000-0001-5995-6494", "researcher": {"href": "https://publications.scilifelab.se/researcher/c4d84c40612d48f280d4ead25558d835.json"}}, {"family": "Krokan", "given": "Hans E", "initials": "HE"}, {"family": "Arvidsson", "given": "Per I", "initials": "PI", "orcid": "0000-0002-9453-6812", "researcher": {"href": "https://publications.scilifelab.se/researcher/ae064b90b750457e80e974947f2dfc7a.json"}}, {"family": "Scobie", "given": "Martin", "initials": "M"}, {"family": "Meiser", "given": "Johannes", "initials": "J"}, {"family": "Stenmark", "given": "P\u00e5l", "initials": "P", "orcid": "0000-0003-4777-3417", "researcher": {"href": "https://publications.scilifelab.se/researcher/d97eba9f5edf4d76a5259c4baa8366c5.json"}}, {"family": "Berglund", "given": "Ulrika Warpman", "initials": "UW"}, {"family": "Homan", "given": "Evert J", "initials": "EJ"}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications.scilifelab.se/researcher/3d7256c271ea4adea404d4ff355f804e.json"}}], "type": "journal article", "published": "2022-02-00", "journal": {"title": "Nat Cancer", "issn": "2662-1347", "volume": "3", "issue": "2", "pages": "156-172", "issn-l": null}, "abstract": "The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors.", "doi": "10.1038/s43018-022-00331-y", "pmid": "35228749", "labels": {"Drug Discovery and Development": "Collaborative"}, "xrefs": [{"db": "pii", "key": "10.1038/s43018-022-00331-y"}, {"db": "pmc", "key": "PMC8885417"}], "notes": [], "created": "2022-05-07T05:35:33.240Z", "modified": "2025-10-17T13:05:07.816Z"}, {"entity": "publication", "iuid": "08a45a5b61b8441ea51d9b53a518fc25", "links": {"self": {"href": "https://publications.scilifelab.se/publication/08a45a5b61b8441ea51d9b53a518fc25.json"}, "display": {"href": "https://publications.scilifelab.se/publication/08a45a5b61b8441ea51d9b53a518fc25"}}, "title": "Development of a chemical probe against NUDT15.", "authors": [{"family": "Zhang", "given": "Si Min", "initials": "SM", "orcid": "0000-0001-7763-603X", "researcher": {"href": "https://publications.scilifelab.se/researcher/1eac01c3a53d4940ade49b24f13dd214.json"}}, {"family": "Desroses", "given": "Matthieu", "initials": "M", "orcid": "0000-0003-4152-3855", "researcher": {"href": "https://publications.scilifelab.se/researcher/b232b70751004e9ea6b547533f901376.json"}}, {"family": "Hagenkort", "given": "Anna", "initials": "A"}, {"family": "Valerie", "given": "Nicholas C K", "initials": "NCK"}, {"family": "Rehling", "given": "Daniel", "initials": "D", "orcid": "0000-0002-8627-3469", "researcher": {"href": "https://publications.scilifelab.se/researcher/a4d521579d594e44b783a8d2e9fb98bb.json"}}, {"family": "Carter", "given": "Megan", "initials": "M"}, {"family": "Wallner", "given": "Olov", "initials": "O"}, {"family": "Koolmeister", "given": "Tobias", "initials": "T"}, {"family": "Throup", "given": "Adam", "initials": "A"}, {"family": "Jemth", "given": "Ann-Sofie", "initials": "AS"}, {"family": "Alml\u00f6f", "given": "Ingrid", "initials": "I"}, {"family": "Loseva", "given": "Olga", "initials": "O"}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T", "orcid": "0000-0002-8145-7808", "researcher": {"href": "https://publications.scilifelab.se/researcher/e13df787cb884549bcf333aba4e6f010.json"}}, {"family": "Axelsson", "given": "Hanna", "initials": "H", "orcid": "0000-0003-2365-1749", "researcher": {"href": "https://publications.scilifelab.se/researcher/63b88c4d11c443f39121c6d93fcff1f0.json"}}, {"family": "Regmi", "given": "Shruti", "initials": "S"}, {"family": "Sarno", "given": "Antonio", "initials": "A"}, {"family": "Kr\u00e4mer", "given": "Andreas", "initials": "A"}, {"family": "Pudelko", "given": "Linda", "initials": "L"}, {"family": "Br\u00e4utigam", "given": "Lars", "initials": "L"}, {"family": "Rasti", "given": "Azita", "initials": "A"}, {"family": "G\u00f6ttmann", "given": "Mona", "initials": "M"}, {"family": "Wiita", "given": "Elis\u00e9e", "initials": "E"}, {"family": "Kutzner", "given": "Juliane", "initials": "J"}, {"family": "Schaller", "given": "Torsten", "initials": "T", "orcid": "0000-0001-9597-4112", "researcher": {"href": "https://publications.scilifelab.se/researcher/c74944db1b4f4fe4a09079f417f8eec6.json"}}, {"family": "Kalder\u00e9n", "given": "Christina", "initials": "C"}, {"family": "C\u00e1zares-K\u00f6rner", "given": "Armando", "initials": "A"}, {"family": "Page", "given": "Brent D G", "initials": "BDG"}, {"family": "Krimpenfort", "given": "Rosa", "initials": "R"}, {"family": "Eshtad", "given": "Saeed", "initials": "S", "orcid": "0000-0001-6763-4700", "researcher": {"href": "https://publications.scilifelab.se/researcher/edf4a705cae045feb64d1d9c7f8d9646.json"}}, {"family": "Altun", "given": "Mikael", "initials": "M", "orcid": "0000-0002-6937-6124", "researcher": {"href": "https://publications.scilifelab.se/researcher/4317b773615e476694840e907b7b1a0c.json"}}, {"family": "Rudd", "given": "Sean G", "initials": "SG", "orcid": "0000-0002-4368-3855", "researcher": {"href": "https://publications.scilifelab.se/researcher/cf1e23d9748e4868a4b5e966e423b1a9.json"}}, {"family": "Knapp", "given": "Stefan", "initials": "S", "orcid": "0000-0001-5995-6494", "researcher": {"href": "https://publications.scilifelab.se/researcher/c4d84c40612d48f280d4ead25558d835.json"}}, {"family": "Scobie", "given": "Martin", "initials": "M"}, {"family": "Homan", "given": "Evert J", "initials": "EJ"}, {"family": "Berglund", "given": "Ulrika Warpman", "initials": "UW", "orcid": "0000-0002-6372-1396", "researcher": {"href": "https://publications.scilifelab.se/researcher/a74c79d4b11346a4918f536b5a678e12.json"}}, {"family": "Stenmark", "given": "P\u00e5l", "initials": "P", "orcid": "0000-0003-4777-3417", "researcher": {"href": "https://publications.scilifelab.se/researcher/d97eba9f5edf4d76a5259c4baa8366c5.json"}}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications.scilifelab.se/researcher/3d7256c271ea4adea404d4ff355f804e.json"}}], "type": "journal article", "published": "2020-10-00", "journal": {"title": "Nat. Chem. Biol.", "issn": "1552-4469", "volume": "16", "issue": "10", "pages": "1120-1128", "issn-l": "1552-4450"}, "abstract": "The NUDIX hydrolase NUDT15 was originally implicated in sanitizing oxidized nucleotides, but was later shown to hydrolyze the active thiopurine metabolites, 6-thio-(d)GTP, thereby dictating the clinical response of this standard-of-care treatment for leukemia and inflammatory diseases. Nonetheless, its physiological roles remain elusive. Here, we sought to develop small-molecule NUDT15 inhibitors to elucidate its biological functions and potentially to improve NUDT15-dependent chemotherapeutics. Lead compound TH1760 demonstrated low-nanomolar biochemical potency through direct and specific binding into the NUDT15 catalytic pocket and engaged cellular NUDT15 in the low-micromolar range. We also employed thiopurine potentiation as a proxy functional readout and demonstrated that TH1760 sensitized cells to 6-thioguanine through enhanced accumulation of 6-thio-(d)GTP in nucleic acids. A biochemically validated, inactive structural analog, TH7285, confirmed that increased thiopurine toxicity takes place via direct NUDT15 inhibition. In conclusion, TH1760 represents the first chemical probe for interrogating NUDT15 biology and potential therapeutic avenues.", "doi": "10.1038/s41589-020-0592-z", "pmid": "32690945", "labels": {"Protein Science Facility (PSF)": "Service", "Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [{"db": "pii", "key": "10.1038/s41589-020-0592-z"}, {"db": "pmc", "key": "PMC7610571"}, {"db": "mid", "key": "EMS118347"}], "notes": [], "created": "2020-09-25T11:44:11.217Z", "modified": "2025-10-17T13:04:28.262Z"}]}