{"entity": "researcher", "timestamp": "2026-08-11T08:52:52.714Z", "family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T", "orcid": "0000-0002-8145-7808", "affiliations": ["Chemical Biology Consortium Sweden, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics Karolinska Institutet SE-171 65 Solna SWEDEN.", "Mechanistic Biology & Profiling, Discovery Sciences, R&D AstraZeneca SE-431 83 G\u00f6teborg SWEDEN."], "links": {"self": {"href": "https://publications.scilifelab.se/researcher/e13df787cb884549bcf333aba4e6f010.json"}, "display": {"href": "https://publications.scilifelab.se/researcher/e13df787cb884549bcf333aba4e6f010"}}, "publications": [{"entity": "publication", "iuid": "d0227fdc5b3843deb2096267d97646b6", "links": {"self": {"href": "https://publications.scilifelab.se/publication/d0227fdc5b3843deb2096267d97646b6.json"}, "display": {"href": "https://publications.scilifelab.se/publication/d0227fdc5b3843deb2096267d97646b6"}}, "title": "Targeting TUBG1 in RB1\u2010negative tumors", "authors": [{"family": "Lindstr\u00f6m", "given": "Lisa", "initials": "L", "orcid": "0009-0008-4510-4635", "researcher": {"href": "https://publications.scilifelab.se/researcher/1091020b47274bfcb2f03a329057d7ae.json"}}, {"family": "Zhou", "given": "Jingkai", "initials": "J", "orcid": "0000-0002-9867-3486", "researcher": {"href": "https://publications.scilifelab.se/researcher/5dc6dcbd404c47eca422a2167085492e.json"}}, {"family": "Villoutreix", "given": "Bruno O", "initials": "BO", "orcid": "0000-0002-6456-7730", "researcher": {"href": "https://publications.scilifelab.se/researcher/faac02c89da248e4b2b393614365c304.json"}}, {"family": "Malycheva", "given": "Darina", "initials": "D"}, {"family": "Otrocka", "given": "Magdalena", "initials": "M", "orcid": "0000-0002-2139-8236", "researcher": {"href": "https://publications.scilifelab.se/researcher/f60f84f70b744033b0c94b6d24e1c405.json"}}, {"family": "Gustavsson", "given": "Anna\u2010Lena", "initials": "A", "orcid": "0000-0003-4332-2336", "researcher": {"href": "https://publications.scilifelab.se/researcher/6b014ef7ea0d461b8e2ddb87506b1252.json"}}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T", "orcid": "0000-0002-8145-7808", "researcher": {"href": "https://publications.scilifelab.se/researcher/e13df787cb884549bcf333aba4e6f010.json"}}, {"family": "Bliman", "given": "David", "initials": "D", "orcid": "0000-0003-0487-8366", "researcher": {"href": "https://publications.scilifelab.se/researcher/7e29451fca1644f3a6fd2bd4bbff9594.json"}}, {"family": "Shameem", "given": "Muhammad Anwar", "initials": "MA", "orcid": "0000-0001-6173-3417", "researcher": {"href": "https://publications.scilifelab.se/researcher/7c7fb16605874dfe93c1343f6ab32e67.json"}}, {"family": "Straw", "given": "Megan", "initials": "M"}, {"family": "Riesbeck", "given": "Kristian", "initials": "K", "orcid": "0000-0001-6274-6965", "researcher": {"href": "https://publications.scilifelab.se/researcher/d757ccad30b043748c8fe48a7308210c.json"}}, {"family": "Olsson", "given": "Roger", "initials": "R", "orcid": "0000-0002-7107-3472", "researcher": {"href": "https://publications.scilifelab.se/researcher/f3e5a72515bf44e98f43d4690c6e577e.json"}}, {"family": "Alvarado\u2010Kristensson", "given": "Maria", "initials": "M", "orcid": "0000-0003-0598-7986", "researcher": {"href": "https://publications.scilifelab.se/researcher/70ee81797eff452fa037821f293d8673.json"}}], "type": "journal-article", "published": "2025-03-15", "journal": {"title": "The FASEB Journal", "issn": "0892-6638", "volume": "39", "issue": "5", "issn-l": "0892-6638"}, "abstract": null, "doi": "10.1096/fj.202403180rr", "pmid": null, "labels": {"Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [], "notes": [], "created": "2025-04-23T10:27:30.624Z", "modified": "2025-10-17T13:04:26.785Z"}, {"entity": "publication", "iuid": "e2e453cf6e8f4cdba5b424821324021d", "links": {"self": {"href": "https://publications.scilifelab.se/publication/e2e453cf6e8f4cdba5b424821324021d.json"}, "display": {"href": "https://publications.scilifelab.se/publication/e2e453cf6e8f4cdba5b424821324021d"}}, "title": "All-photonic kinase inhibitors: light-controlled release-and-report inhibition.", "authors": [{"family": "Fleming", "given": "Cassandra L", "initials": "CL", "orcid": "0000-0002-7730-7305", "researcher": {"href": "https://publications.scilifelab.se/researcher/a29a83ba2b3444768821489dc667279e.json"}}, {"family": "Benitez-Martin", "given": "Carlos", "initials": "C", "orcid": "0000-0003-1821-9388", "researcher": {"href": "https://publications.scilifelab.se/researcher/d1fcdd6e053b462998fe7f463be60d96.json"}}, {"family": "Bernson", "given": "Elin", "initials": "E", "orcid": "0000-0001-6414-5725", "researcher": {"href": "https://publications.scilifelab.se/researcher/ced3ddbde2ad4f28b28b622d817b2e59.json"}}, {"family": "Xu", "given": "Yongjin", "initials": "Y"}, {"family": "Kristenson", "given": "Linnea", "initials": "L"}, {"family": "Inghardt", "given": "Tord", "initials": "T", "orcid": "0000-0002-4804-9474", "researcher": {"href": "https://publications.scilifelab.se/researcher/bc8a41790a034fe48cce02c8e7034e34.json"}}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T", "orcid": "0000-0002-8145-7808", "researcher": {"href": "https://publications.scilifelab.se/researcher/e13df787cb884549bcf333aba4e6f010.json"}}, {"family": "Thor\u00e9n", "given": "Fredrik B", "initials": "FB", "orcid": "0000-0003-2167-7451", "researcher": {"href": "https://publications.scilifelab.se/researcher/6e8a4846c6f44c0793f4cb5d73b66de6.json"}}, {"family": "Gr\u00f8tli", "given": "Morten", "initials": "M", "orcid": "0000-0003-3621-4222", "researcher": {"href": "https://publications.scilifelab.se/researcher/764706606bcb4afba1150af332c0f124.json"}}, {"family": "Andr\u00e9asson", "given": "Joakim", "initials": "J", "orcid": "0000-0003-4695-7943", "researcher": {"href": "https://publications.scilifelab.se/researcher/28eb5affb5664c54be9171dfce6bea15.json"}}], "type": "journal article", "published": "2024-05-08", "journal": {"title": "Chem. Sci.", "issn": "2041-6520", "volume": "15", "issue": "18", "pages": "6897-6905", "issn-l": null}, "abstract": "Light-responsive molecular tools targeting kinases affords one the opportunity to study the underlying cellular function of selected kinases. In efforts to externally control lymphocyte-specific protein tyrosine kinase (LCK) activity, the development of release-and-report LCK inhibitors is described, in which (i) the release of the active kinase inhibitor can be controlled externally with light; and (ii) fluorescence is employed to report both the release and binding of the active kinase inhibitor. This introduces an unprecedented all-photonic method for users to both control and monitor real-time inhibitory activity. A functional cellular assay demonstrated light-mediated LCK inhibition in natural killer cells. The use of coumarin-derived caging groups resulted in rapid cellular uptake and non-specific intracellular localisation, while a BODIPY-derived caging group predominately localised in the cellular membrane. This concept of release-and-report inhibitors has the potential to be extended to other biorelevant targets where both spatiotemporal control in a cellular setting and a reporting mechanism would be beneficial.", "doi": "10.1039/d4sc00390j", "pmid": "38725520", "labels": {"Integrated Microscopy Technologies Gothenburg": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC11077529"}, {"db": "pii", "key": "d4sc00390j"}], "notes": [], "created": "2024-11-15T12:04:25.342Z", "modified": "2024-11-15T12:04:25.556Z"}, {"entity": "publication", "iuid": "15722bb1086f44f7bd700d32703ab2a9", "links": {"self": {"href": "https://publications.scilifelab.se/publication/15722bb1086f44f7bd700d32703ab2a9.json"}, "display": {"href": "https://publications.scilifelab.se/publication/15722bb1086f44f7bd700d32703ab2a9"}}, "title": "Identification and evaluation of small-molecule inhibitors against the dNTPase SAMHD1viaa comprehensive screening funnel", "authors": [{"family": "Zhang", "given": "Si Min", "initials": "SM", "orcid": "0000-0001-7763-603X", "researcher": {"href": "https://publications.scilifelab.se/researcher/1eac01c3a53d4940ade49b24f13dd214.json"}}, {"family": "Paulin", "given": "Cynthia B J", "initials": "CBJ", "orcid": "0000-0002-5698-7962", "researcher": {"href": "https://publications.scilifelab.se/researcher/f54dd3938c0640f1b770a3b52baba6d9.json"}}, {"family": "Michel", "given": "Maurice", "initials": "M", "orcid": "0000-0003-3261-2493", "researcher": {"href": "https://publications.scilifelab.se/researcher/4f7cb5d695254481b745f86a824ac1b5.json"}}, {"family": "Marttila", "given": "Petra", "initials": "P", "orcid": "0000-0002-0115-8067", "researcher": {"href": "https://publications.scilifelab.se/researcher/2e3e92bdf843456784f98d3b521d2ccd.json"}}, {"family": "Yag\u00fce-Capilla", "given": "Miriam", "initials": "M"}, {"family": "Bwanika", "given": "Henri Colyn", "initials": "HC"}, {"family": "Shu", "given": "Huazhang", "initials": "H"}, {"family": "Vekatram", "given": "Rajagopal Papagudi", "initials": "RP"}, {"family": "Wiita", "given": "Elis\u00e9e", "initials": "E"}, {"family": "Jemth", "given": "Ann Sofie", "initials": "AS", "orcid": "0000-0002-7550-1833", "researcher": {"href": "https://publications.scilifelab.se/researcher/fd07c6c543544af1a904e039f73ba857.json"}}, {"family": "Alml\u00f6f", "given": "Ingrid", "initials": "I"}, {"family": "Loseva", "given": "Olga", "initials": "O"}, {"family": "Ortis", "given": "Florian", "initials": "F"}, {"family": "Dirks", "given": "Christopher", "initials": "C", "orcid": "0000-0003-4503-8291", "researcher": {"href": "https://publications.scilifelab.se/researcher/2188fde32a784feaa40cfff1e18c1125.json"}}, {"family": "Koolmeister", "given": "Tobias", "initials": "T"}, {"family": "Linde", "given": "Erika", "initials": "E"}, {"family": "Lee", "given": "Sun", "initials": "S"}, {"family": "Llona-Minguez", "given": "Sabin", "initials": "S", "orcid": "0000-0003-3187-722X", "researcher": {"href": "https://publications.scilifelab.se/researcher/437b1f98ad21471f884226ed89a3da12.json"}}, {"family": "Haraldsson", "given": "Martin", "initials": "M", "orcid": "0000-0003-0743-7830", "researcher": {"href": "https://publications.scilifelab.se/researcher/42031e3e48ba47f896b74bfb733cdeff.json"}}, {"family": "Str\u00f6mberg", "given": "Kia", "initials": "K"}, {"family": "Homan", "given": "Evert J", "initials": "EJ"}, {"family": "Scobie", "given": "Martin", "initials": "M", "orcid": "0000-0002-7073-8495", "researcher": {"href": "https://publications.scilifelab.se/researcher/87c041a8b3414f5db02873dc8013806b.json"}}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T", "orcid": "0000-0002-8145-7808", "researcher": {"href": "https://publications.scilifelab.se/researcher/e13df787cb884549bcf333aba4e6f010.json"}}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications.scilifelab.se/researcher/3d7256c271ea4adea404d4ff355f804e.json"}}, {"family": "Rudd", "given": "Sean G", "initials": "SG", "orcid": "0000-0002-4368-3855", "researcher": {"href": "https://publications.scilifelab.se/researcher/cf1e23d9748e4868a4b5e966e423b1a9.json"}}], "type": "posted-content", "published": "2023-01-18", "journal": {"title": "biorxiv", "issn": null, "issn-l": null, "volume": null, "issue": null, "pages": null}, "abstract": null, "doi": "10.1101/2023.01.17.524275", "pmid": null, "labels": {"Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [], "notes": [], "created": "2023-10-18T18:41:03.768Z", "modified": "2025-12-18T19:56:49.749Z"}, {"entity": "publication", "iuid": "238d3aa204584626b4262aea39c30cc5", "links": {"self": {"href": "https://publications.scilifelab.se/publication/238d3aa204584626b4262aea39c30cc5.json"}, "display": {"href": "https://publications.scilifelab.se/publication/238d3aa204584626b4262aea39c30cc5"}}, "title": "Inhibition of the ubiquitin-proteasome system by an NQO1-activatable compound.", "authors": [{"family": "Giovannucci", "given": "Tatiana A", "initials": "TA", "orcid": "0000-0001-8978-6318", "researcher": {"href": "https://publications.scilifelab.se/researcher/56b2f3f196874ef8b62a8768286c136a.json"}}, {"family": "Salomons", "given": "Florian A", "initials": "FA"}, {"family": "Haraldsson", "given": "Martin", "initials": "M"}, {"family": "Elfman", "given": "Lotta H M", "initials": "LHM"}, {"family": "Wickstr\u00f6m", "given": "Malin", "initials": "M", "orcid": "0000-0001-5214-9956", "researcher": {"href": "https://publications.scilifelab.se/researcher/2bd8b895bc0a4dca89c4170f85d3ebb4.json"}}, {"family": "Young", "given": "Patrick", "initials": "P"}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T", "orcid": "0000-0002-8145-7808", "researcher": {"href": "https://publications.scilifelab.se/researcher/e13df787cb884549bcf333aba4e6f010.json"}}, {"family": "Eirich", "given": "J\u00fcrgen", "initials": "J", "orcid": "0000-0003-0963-1872", "researcher": {"href": "https://publications.scilifelab.se/researcher/ec48b74a3727482d944088601c310a38.json"}}, {"family": "Altun", "given": "Mikael", "initials": "M", "orcid": "0000-0002-6937-6124", "researcher": {"href": "https://publications.scilifelab.se/researcher/4317b773615e476694840e907b7b1a0c.json"}}, {"family": "Jafari", "given": "Rozbeh", "initials": "R", "orcid": "0000-0002-3396-4709", "researcher": {"href": "https://publications.scilifelab.se/researcher/481b2a2329634f9086cf52fb808edea5.json"}}, {"family": "Gustavsson", "given": "Anna-Lena", "initials": "AL"}, {"family": "Johnsen", "given": "John Inge", "initials": "JI", "orcid": "0000-0003-1277-812X", "researcher": {"href": "https://publications.scilifelab.se/researcher/4c5b7b4c780349afacf3063e311c334e.json"}}, {"family": "Dantuma", "given": "Nico P", "initials": "NP", "orcid": "0000-0002-6090-4170", "researcher": {"href": "https://publications.scilifelab.se/researcher/0ccdd02c787d4a699efd24d297040aa0.json"}}], "type": "journal article", "published": "2021-10-06", "journal": {"title": "Cell Death Dis", "issn": "2041-4889", "issn-l": "2041-4889", "volume": "12", "issue": "10", "pages": "914"}, "abstract": "Malignant cells display an increased sensitivity towards drugs that reduce the function of the ubiquitin-proteasome system (UPS), which is the primary proteolytic system for destruction of aberrant proteins. Here, we report on the discovery of the bioactivatable compound CBK77, which causes an irreversible collapse of the UPS, accompanied by a general accumulation of ubiquitylated proteins and caspase-dependent cell death. CBK77 caused accumulation of ubiquitin-dependent, but not ubiquitin-independent, reporter substrates of the UPS, suggesting a selective effect on ubiquitin-dependent proteolysis. In a genome-wide CRISPR interference screen, we identified the redox enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) as a critical mediator of CBK77 activity, and further demonstrated its role as the compound bioactivator. Through affinity-based proteomics, we found that CBK77 covalently interacts with ubiquitin. In vitro experiments showed that CBK77-treated ubiquitin conjugates were less susceptible to disassembly by deubiquitylating enzymes. In vivo efficacy of CBK77 was validated by reduced growth of NQO1-proficient human adenocarcinoma cells in nude mice treated with CBK77. This first-in-class NQO1-activatable UPS inhibitor suggests that it may be possible to exploit the intracellular environment in malignant cells for leveraging the impact of compounds that impair the UPS.", "doi": "10.1038/s41419-021-04191-9", "pmid": "34615851", "labels": {"CRISPR Functional Genomics": "Service", "NGI Stockholm (Genomics Applications)": "Service", "NGI Stockholm (Genomics Production)": "Service", "National Genomics Infrastructure": "Service", "Global Proteomics and Proteogenomics": "Service", "Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [{"db": "pii", "key": "10.1038/s41419-021-04191-9"}, {"db": "pmc", "key": "PMC8494907"}], "notes": [], "created": "2021-10-16T09:54:38.919Z", "modified": "2025-10-17T13:04:28.026Z"}, {"entity": "publication", "iuid": "e3d59e32739d4f7e93ec76c6f809a20d", "links": {"self": {"href": "https://publications.scilifelab.se/publication/e3d59e32739d4f7e93ec76c6f809a20d.json"}, "display": {"href": "https://publications.scilifelab.se/publication/e3d59e32739d4f7e93ec76c6f809a20d"}}, "title": "Design and development of a photoswitchable DFG-out kinase inhibitor.", "authors": [{"family": "Xu", "given": "Yongjin", "initials": "Y"}, {"family": "Gao", "given": "Chunxia", "initials": "C"}, {"family": "H\u00e5versen", "given": "Liliana", "initials": "L"}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T", "orcid": "0000-0002-8145-7808", "researcher": {"href": "https://publications.scilifelab.se/researcher/e13df787cb884549bcf333aba4e6f010.json"}}, {"family": "Andr\u00e9asson", "given": "Joakim", "initials": "J", "orcid": "0000-0003-4695-7943", "researcher": {"href": "https://publications.scilifelab.se/researcher/28eb5affb5664c54be9171dfce6bea15.json"}}, {"family": "Gr\u00f8tli", "given": "Morten", "initials": "M", "orcid": "0000-0003-3621-4222", "researcher": {"href": "https://publications.scilifelab.se/researcher/764706606bcb4afba1150af332c0f124.json"}}], "type": "journal article", "published": "2021-09-30", "journal": {"title": "Chem. Commun. (Camb.)", "issn": "1364-548X", "issn-l": "1359-7345", "volume": "57", "issue": "78", "pages": "10043-10046"}, "abstract": "We report the synthesis and characterisation of a photoswitchable DFG-out kinase inhibitor. Photocontrol of the target kinase in both enzymatic and living cell assays is demonstrated.", "doi": "10.1039/d1cc04125h", "pmid": "34505602", "labels": {"Chemical Biology Consortium Sweden": "Service"}, "xrefs": [], "notes": [], "created": "2021-11-03T11:52:31.970Z", "modified": "2025-10-17T13:04:28.037Z"}, {"entity": "publication", "iuid": "0ad99a1125484d83985204103a367b5c", "links": {"self": {"href": "https://publications.scilifelab.se/publication/0ad99a1125484d83985204103a367b5c.json"}, "display": {"href": "https://publications.scilifelab.se/publication/0ad99a1125484d83985204103a367b5c"}}, "title": "A FabG inhibitor targeting an allosteric binding site inhibits several orthologs from Gram-negative ESKAPE pathogens.", "authors": [{"family": "Vella", "given": "Peter", "initials": "P"}, {"family": "Rudraraju", "given": "Reshma Srilakshmi", "initials": "RS"}, {"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": "Almqvist", "given": "Helena", "initials": "H"}, {"family": "Vallin", "given": "Michaela", "initials": "M", "orcid": "0000-0001-5103-492X", "researcher": {"href": "https://publications.scilifelab.se/researcher/934c06b4537340558adbf24683a58f76.json"}}, {"family": "Schneider", "given": "Gunter", "initials": "G"}, {"family": "Schnell", "given": "Robert", "initials": "R", "orcid": "0000-0001-7530-3629", "researcher": {"href": "https://publications.scilifelab.se/researcher/85936b030f29480a86953b8367fc97f3.json"}}], "type": "journal article", "published": "2021-01-15", "journal": {"title": "Bioorg. Med. Chem.", "issn": "1464-3391", "issn-l": "0968-0896", "volume": "30", "issue": null, "pages": "115898"}, "abstract": "The spread of antibiotic resistance within the ESKAPE group of human pathogenic bacteria poses severe challenges in the treatment of infections and maintenance of safe hospital environments. This motivates efforts to validate novel target proteins within these species that could be pursued as potential targets for antibiotic development. Genetic data suggest that the enzyme FabG, which is part of the bacterial fatty acid biosynthetic system FAS-II, is essential in several ESKAPE pathogens. FabG catalyzes the NADPH dependent reduction of 3-keto-acyl-ACP during fatty acid elongation, thus enabling lipid supply for production and maintenance of the cell envelope. Here we report on small-molecule screening on the FabG enzymes from A. baumannii and S. typhimurium to identify a set of \u00b5M inhibitors, with the most potent representative (1) demonstrating activity against six FabG-orthologues. A co-crystal structure with FabG from A. baumannii (PDB:6T65) confirms inhibitor binding at an allosteric site located in the subunit interface, as previously demonstrated for other sub-\u00b5M inhibitors of FabG from P. aeruginosa. We show that inhibitor binding distorts the oligomerization interface in the FabG tetramer and displaces crucial residues involved in the interaction with the co-substrate NADPH. These observations suggest a conserved allosteric site across the FabG family, which can be potentially targeted for interference with fatty acid biosynthesis in clinically relevant ESKAPE pathogens.", "doi": "10.1016/j.bmc.2020.115898", "pmid": "33388594", "labels": {"Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [{"db": "pii", "key": "S0968-0896(20)30728-8"}], "notes": [], "created": "2021-01-04T16:14:43.555Z", "modified": "2025-10-17T13:04:28.190Z"}, {"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"}, {"entity": "publication", "iuid": "1dc0cba1f4bc4a469774e55e3d8fe100", "links": {"self": {"href": "https://publications.scilifelab.se/publication/1dc0cba1f4bc4a469774e55e3d8fe100.json"}, "display": {"href": "https://publications.scilifelab.se/publication/1dc0cba1f4bc4a469774e55e3d8fe100"}}, "title": "Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro-Oxindole Dihydroquinazolinones as IRAP Inhibitors.", "authors": [{"family": "Engen", "given": "Karin", "initials": "K"}, {"family": "Vanga", "given": "Sudarsana Reddy", "initials": "SR"}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T", "orcid": "0000-0002-8145-7808", "researcher": {"href": "https://publications.scilifelab.se/researcher/e13df787cb884549bcf333aba4e6f010.json"}}, {"family": "Agalo", "given": "Faith", "initials": "F"}, {"family": "Konda", "given": "Vivek", "initials": "V"}, {"family": "Jensen", "given": "Annika Jenmalm", "initials": "AJ"}, {"family": "\u00c5qvist", "given": "Johan", "initials": "J", "orcid": "0000-0003-2091-0610", "researcher": {"href": "https://publications.scilifelab.se/researcher/9777a1c6e1bd4181bc46dce4be3c2146.json"}}, {"family": "Guti\u00e9rrez-de-Ter\u00e1n", "given": "Hugo", "initials": "H"}, {"family": "Hallberg", "given": "Mathias", "initials": "M"}, {"family": "Larhed", "given": "Mats", "initials": "M", "orcid": "0000-0001-6258-0635", "researcher": {"href": "https://publications.scilifelab.se/researcher/011ee4a03a534099a5d71b0fdd6dbe81.json"}}, {"family": "Rosenstr\u00f6m", "given": "Ulrika", "initials": "U", "orcid": "0000-0002-0817-8140", "researcher": {"href": "https://publications.scilifelab.se/researcher/6cd5910fdd8c4f1b87d18223b11e3821.json"}}], "type": "journal article", "published": "2020-03-00", "journal": {"volume": "9", "issn": "2191-1363", "issue": "3", "pages": "325-337", "title": "ChemistryOpen", "issn-l": "2191-1363"}, "abstract": "Insulin-regulated aminopeptidase (IRAP) is a new potential macromolecular target for drugs aimed for treatment of cognitive disorders. Inhibition of IRAP by angiotensin IV (Ang IV) improves the memory and learning in rats. The majority of the known IRAP inhibitors are peptidic in character and suffer from poor pharmacokinetic properties. Herein, we present a series of small non-peptide IRAP inhibitors derived from a spiro-oxindole dihydroquinazolinone screening hit (pIC50 5.8). The compounds were synthesized either by a simple microwave (MW)-promoted three-component reaction, or by a two-step one-pot procedure. For decoration of the oxindole ring system, rapid MW-assisted Suzuki-Miyaura cross-couplings (1 min) were performed. A small improvement of potency (pIC50 6.6 for the most potent compound) and an increased solubility could be achieved. As deduced from computational modelling and MD simulations it is proposed that the S-configuration of the spiro-oxindole dihydroquinazolinones accounts for the inhibition of IRAP.", "doi": "10.1002/open.201900344", "pmid": "32154052", "labels": {"Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [{"db": "pii", "key": "OPEN201900344"}, {"db": "pmc", "key": "PMC7050655"}], "notes": [], "created": "2020-03-04T13:11:28.870Z", "modified": "2025-10-17T13:04:28.346Z"}, {"entity": "publication", "iuid": "93040a08682f4965ad6b27fe955b74d1", "links": {"self": {"href": "https://publications.scilifelab.se/publication/93040a08682f4965ad6b27fe955b74d1.json"}, "display": {"href": "https://publications.scilifelab.se/publication/93040a08682f4965ad6b27fe955b74d1"}}, "title": "Perspective on CETSA Literature: Toward More Quantitative Data Interpretation.", "authors": [{"family": "Seashore-Ludlow", "given": "Brinton", "initials": "B", "orcid": "0000-0001-8658-5967", "researcher": {"href": "https://publications.scilifelab.se/researcher/4645bc97a8024c548111802101b83571.json"}}, {"family": "Axelsson", "given": "Hanna", "initials": "H"}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T", "orcid": "0000-0002-8145-7808", "researcher": {"href": "https://publications.scilifelab.se/researcher/e13df787cb884549bcf333aba4e6f010.json"}}], "type": "journal article", "published": "2020-02-00", "journal": {"volume": "25", "issn": "2472-5560", "issue": "2", "pages": "118-126", "title": "SLAS DISCOVERY: Advancing Life Sciences R&D", "issn-l": "2472-5552"}, "abstract": "The cellular thermal shift assay (CETSA) was introduced in 2013 to investigate drug-target engagement inside live cells and tissues. As with all thermal shift assays, the response measured by CETSA is not simply governed by ligand affinity to the investigated target protein, but the thermodynamics and kinetics of ligand binding and protein unfolding also contribute to the observed protein stabilization. This limitation is commonly neglected in current applications of the method to validate the target of small-molecule probes. Instead, there is an eagerness to make direct comparisons of CETSA measurements with functional and phenotypic readouts from cells at 37 \u00b0C. Here, we present a perspective of the early CETSA literature and put the accumulated data into a quantitative context. The analysis includes annotation of ~270 peer-reviewed papers, the majority of which do not consider the underlying biophysical basis of CETSA. We also detail what future technology developments are needed to enable CETSA-based optimization of structure-activity relationships and more appropriate comparisons of these data with functional or phenotypic responses. Finally, we describe ongoing developments in assay formats that allow for CETSA measurements at single-cell resolution, with the aspiration to allow differentiation in cellular target engagement between cells in co-cultures and more complex models, such as organoids and potentially even tissue.", "doi": "10.1177/2472555219884524", "pmid": "31665966", "labels": {"Chemical Biology Consortium Sweden": "Technology development"}, "xrefs": [], "notes": [], "created": "2019-11-07T18:36:29.528Z", "modified": "2025-10-17T13:04:28.381Z"}, {"entity": "publication", "iuid": "9d5f64c458b7473dafcb19fadc715097", "links": {"self": {"href": "https://publications.scilifelab.se/publication/9d5f64c458b7473dafcb19fadc715097.json"}, "display": {"href": "https://publications.scilifelab.se/publication/9d5f64c458b7473dafcb19fadc715097"}}, "title": "A Phenotypic Screening Assay Identifies Modulators of Diamond Blackfan Anemia.", "authors": [{"family": "Siva", "given": "Kavitha", "initials": "K"}, {"family": "Ek", "given": "Fredrik", "initials": "F"}, {"family": "Chen", "given": "Jun", "initials": "J"}, {"family": "Ghani Alattar", "given": "Abdul", "initials": "A", "orcid": "0000-0002-0319-4416", "researcher": {"href": "https://publications.scilifelab.se/researcher/28c63e788c764cdd9c88ae3317d91ab0.json"}}, {"family": "Sigmundsson", "given": "Kristmundur", "initials": "K"}, {"family": "Olsson", "given": "Roger", "initials": "R"}, {"family": "Wlodarski", "given": "Marcin", "initials": "M"}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T", "orcid": "0000-0002-8145-7808", "researcher": {"href": "https://publications.scilifelab.se/researcher/e13df787cb884549bcf333aba4e6f010.json"}}, {"family": "Flygare", "given": "Johan", "initials": "J"}], "type": "journal article", "published": "2019-03-00", "journal": {"volume": "24", "issn": "2472-5560", "issue": "3", "pages": "304-313", "title": "SLAS DISCOVERY: Advancing Life Sciences R&D", "issn-l": "2472-5552"}, "abstract": "Diamond-Blackfan anemia (DBA) is a bone marrow failure syndrome caused by mutations in ribosomal protein genes. Pathogenic mechanisms are poorly understood but involve severely reduced proliferation of erythroid precursors. Because current DBA therapies are ineffective and associated with severe side effects, disease-specific therapies are urgently needed. We hypothesized that druggable molecular pathways underlying the defect can be revealed through phenotypic small-molecule screens. Accordingly, a screening assay was developed using c-kit+ fetal liver erythroid progenitors from a doxycycline-inducible DBA mouse model. The addition of doxycycline to the culture medium induces the phenotype and reduces proliferation to <10% of normal, such that rescue of proliferation can be used as a simple readout for screening. Here, we describe the assay rationale and efforts toward validation of a microtiter plate-compatible assay and its application in a pilot screen of 3871 annotated compounds. Ten hits demonstrated concentration-dependent activity, and we report a brief follow-up of one of these compounds. In conclusion, we established a robust scalable assay for screening molecules that rescue erythropoiesis in DBA.", "doi": "10.1177/2472555218823531", "pmid": "30784369", "labels": {"Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [], "notes": [], "created": "2019-02-25T10:11:24.200Z", "modified": "2025-10-17T13:04:28.609Z"}, {"entity": "publication", "iuid": "79f9470c7f03483f9ecb1a5d6a7dd093", "links": {"self": {"href": "https://publications.scilifelab.se/publication/79f9470c7f03483f9ecb1a5d6a7dd093.json"}, "display": {"href": "https://publications.scilifelab.se/publication/79f9470c7f03483f9ecb1a5d6a7dd093"}}, "title": "Early Perspective: Microplate Applications of the Cellular Thermal Shift Assay (CETSA)", "authors": [{"family": "Seashore-Ludlow", "given": "Brinton", "initials": "B", "orcid": "0000-0001-8658-5967", "researcher": {"href": "https://publications.scilifelab.se/researcher/4645bc97a8024c548111802101b83571.json"}}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T", "orcid": "0000-0002-8145-7808", "researcher": {"href": "https://publications.scilifelab.se/researcher/e13df787cb884549bcf333aba4e6f010.json"}}], "type": "journal article", "published": "2016-12-00", "journal": {"title": "J Biomol Screen", "issn": "1552-454X", "issn-l": "1087-0571", "volume": "21", "issue": "10", "pages": "1019-1033"}, "abstract": "The cellular thermal shift assay (CETSA) was introduced in 2013 as a means to assess drug binding in complex environments such as cell lysates, live cells, and even tissues. The assay principle relies on the well-proven biophysical concept of ligand-induced thermal stabilization of proteins, which in CETSA applications is measured as a persistent presence of soluble protein at elevated temperatures. Given its recent development, we have just started to learn about the benefits and pitfalls of the method as it is applied to a growing number of protein target classes, the majority of which are intracellular soluble proteins. One of the early technology developments concerned the transfer of the original assay procedure from PCR tubes and Western blot detection of soluble protein to a homogeneous assay in high-density microplates. A move to high-throughput formats is essential for a more systematic application in drug discovery settings, as well as in academic efforts for validating chemical probes through studies of structure-activity relationships. This perspective aims at providing an overview of knowledge gained in microplate formatting of CETSA and makes an attempt at forecasting future applications.", "doi": "10.1177/1087057116659256", "pmid": "27401582", "labels": {"Chemical Biology Consortium Sweden": "Technology development"}, "xrefs": [{"db": "pii", "key": "1087057116659256"}], "notes": [], "created": "2017-10-31T13:14:48.893Z", "modified": "2025-10-17T13:04:29.368Z"}, {"entity": "publication", "iuid": "675347d3c50d42f196d814d845d3b268", "links": {"self": {"href": "https://publications.scilifelab.se/publication/675347d3c50d42f196d814d845d3b268.json"}, "display": {"href": "https://publications.scilifelab.se/publication/675347d3c50d42f196d814d845d3b268"}}, "title": "MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool.", "authors": [{"family": "Gad", "given": "Helge", "initials": "H", "orcid": "0000-0001-6530-1443", "researcher": {"href": "https://publications.scilifelab.se/researcher/6273ef3dd1574185af0a83e9ab31bfe5.json"}}, {"family": "Koolmeister", "given": "Tobias", "initials": "T"}, {"family": "Jemth", "given": "Ann-Sofie", "initials": "A", "orcid": "0000-0002-7550-1833", "researcher": {"href": "https://publications.scilifelab.se/researcher/fd07c6c543544af1a904e039f73ba857.json"}}, {"family": "Eshtad", "given": "Saeed", "initials": "S", "orcid": "0000-0001-6763-4700", "researcher": {"href": "https://publications.scilifelab.se/researcher/edf4a705cae045feb64d1d9c7f8d9646.json"}}, {"family": "Jacques", "given": "Sylvain A", "initials": "SA"}, {"family": "Str\u00f6m", "given": "Cecilia E", "initials": "CE"}, {"family": "Svensson", "given": "Linda M", "initials": "LM"}, {"family": "Schultz", "given": "Niklas", "initials": "N"}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T", "orcid": "0000-0002-8145-7808", "researcher": {"href": "https://publications.scilifelab.se/researcher/e13df787cb884549bcf333aba4e6f010.json"}}, {"family": "Einarsdottir", "given": "Berglind Osk", "initials": "BO"}, {"family": "Saleh", "given": "Aljona", "initials": "A"}, {"family": "G\u00f6kt\u00fcrk", "given": "Camilla", "initials": "C", "orcid": "0000-0002-6272-9927", "researcher": {"href": "https://publications.scilifelab.se/researcher/9318cec5020f4c92b8393b20242c0d58.json"}}, {"family": "Baranczewski", "given": "Pawel", "initials": "P", "orcid": "0000-0001-5772-6791", "researcher": {"href": "https://publications.scilifelab.se/researcher/47f7af2466c14275a42aad4a431b2dcb.json"}}, {"family": "Svensson", "given": "Richard", "initials": "R"}, {"family": "Berntsson", "given": "Ronnie P-A", "initials": "RP"}, {"family": "Gustafsson", "given": "Robert", "initials": "R", "orcid": "0000-0002-4854-5531", "researcher": {"href": "https://publications.scilifelab.se/researcher/16dd7e73adad4f85972d1d546bfa6d2a.json"}}, {"family": "Str\u00f6mberg", "given": "Kia", "initials": "K"}, {"family": "Sanjiv", "given": "Kumar", "initials": "K"}, {"family": "Jacques-Cordonnier", "given": "Marie-Caroline", "initials": "M"}, {"family": "Desroses", "given": "Matthieu", "initials": "M", "orcid": "0000-0003-4152-3855", "researcher": {"href": "https://publications.scilifelab.se/researcher/b232b70751004e9ea6b547533f901376.json"}}, {"family": "Gustavsson", "given": "Anna-Lena", "initials": "A", "orcid": "0000-0003-4332-2336", "researcher": {"href": "https://publications.scilifelab.se/researcher/6b014ef7ea0d461b8e2ddb87506b1252.json"}}, {"family": "Olofsson", "given": "Roger", "initials": "R"}, {"family": "Johansson", "given": "Fredrik", "initials": "F", "orcid": "0000-0001-5160-9543", "researcher": {"href": "https://publications.scilifelab.se/researcher/0667c14b327f44fd8a802acd9c3f1fb2.json"}}, {"family": "Homan", "given": "Evert J", "initials": "EJ"}, {"family": "Loseva", "given": "Olga", "initials": "O"}, {"family": "Br\u00e4utigam", "given": "Lars", "initials": "L"}, {"family": "Johansson", "given": "Lars", "initials": "L", "orcid": "0000-0001-7071-4699", "researcher": {"href": "https://publications.scilifelab.se/researcher/7b9129e8ce7846e5b35b50f1ff4493e2.json"}}, {"family": "H\u00f6glund", "given": "Andreas", "initials": "A", "orcid": "0000-0002-1130-374X", "researcher": {"href": "https://publications.scilifelab.se/researcher/70a484451caf40f2a1a196b36bb9c423.json"}}, {"family": "Hagenkort", "given": "Anna", "initials": "A"}, {"family": "Pham", "given": "Therese", "initials": "T"}, {"family": "Altun", "given": "Mikael", "initials": "M", "orcid": "0000-0002-6937-6124", "researcher": {"href": "https://publications.scilifelab.se/researcher/4317b773615e476694840e907b7b1a0c.json"}}, {"family": "Gaugaz", "given": "Fabienne Z", "initials": "FZ"}, {"family": "Vikingsson", "given": "Svante", "initials": "S"}, {"family": "Evers", "given": "Bastiaan", "initials": "B"}, {"family": "Henriksson", "given": "Martin", "initials": "M"}, {"family": "Vallin", "given": "Karl S A", "initials": "KSA"}, {"family": "Wallner", "given": "Olov A", "initials": "OA"}, {"family": "Hammarstr\u00f6m", "given": "Lars G J", "initials": "LGJ"}, {"family": "Wiita", "given": "Elisee", "initials": "E"}, {"family": "Alml\u00f6f", "given": "Ingrid", "initials": "I"}, {"family": "Kalder\u00e9n", "given": "Christina", "initials": "C"}, {"family": "Axelsson", "given": "Hanna", "initials": "H", "orcid": "0000-0003-2365-1749", "researcher": {"href": "https://publications.scilifelab.se/researcher/63b88c4d11c443f39121c6d93fcff1f0.json"}}, {"family": "Djureinovic", "given": "Tatjana", "initials": "T"}, {"family": "Puigvert", "given": "Jordi Carreras", "initials": "JC"}, {"family": "H\u00e4ggblad", "given": "Maria", "initials": "M", "orcid": "0000-0002-3857-1437", "researcher": {"href": "https://publications.scilifelab.se/researcher/c2b5f5d0486a4422b93a626a2cd1583f.json"}}, {"family": "Jeppsson", "given": "Fredrik", "initials": "F"}, {"family": "Martens", "given": "Ulf", "initials": "U"}, {"family": "Lundin", "given": "Cecilia", "initials": "C"}, {"family": "Lundgren", "given": "Bo", "initials": "B"}, {"family": "Granelli", "given": "Ingrid", "initials": "I"}, {"family": "Jensen", "given": "Annika Jenmalm", "initials": "AJ"}, {"family": "Artursson", "given": "Per", "initials": "P", "orcid": "0000-0002-3708-7395", "researcher": {"href": "https://publications.scilifelab.se/researcher/31575936c2714e1eb2f35c12df9a65a8.json"}}, {"family": "Nilsson", "given": "Jonas A", "initials": "JA", "orcid": "0000-0003-0346-6837", "researcher": {"href": "https://publications.scilifelab.se/researcher/27f0581f25124e98b0bd0eef8c3f3331.json"}}, {"family": "Stenmark", "given": "P\u00e5l", "initials": "P", "orcid": "0000-0003-4777-3417", "researcher": {"href": "https://publications.scilifelab.se/researcher/d97eba9f5edf4d76a5259c4baa8366c5.json"}}, {"family": "Scobie", "given": "Martin", "initials": "M", "orcid": "0000-0002-7073-8495", "researcher": {"href": "https://publications.scilifelab.se/researcher/87c041a8b3414f5db02873dc8013806b.json"}}, {"family": "Berglund", "given": "Ulrika Warpman", "initials": "UW", "orcid": "0000-0002-6372-1396", "researcher": {"href": "https://publications.scilifelab.se/researcher/a74c79d4b11346a4918f536b5a678e12.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": "2014-04-10", "journal": {"volume": "508", "issn": "1476-4687", "issue": "7495", "pages": "215-221", "title": "Nature", "issn-l": "0028-0836"}, "abstract": "Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.", "doi": "10.1038/nature13181", "pmid": "24695224", "labels": {"Protein Science Facility (PSF)": null, "Chemical Biology Consortium Sweden": "Collaborative", "Drug Discovery and Development": "Collaborative"}, "xrefs": [{"db": "pii", "key": "nature13181"}], "notes": "Uppsala Drug Optimization and Pharmaceutical Profiling (UDOPP)\r\nADME of Therapeutics (UDOPP)\r\nBiochemical and Cellular Screening", "created": "2017-05-04T14:56:52.658Z", "modified": "2025-10-23T08:56:28.795Z"}]}