{"entity": "researcher", "timestamp": "2026-04-20T22:22:07.192Z", "family": "Gustavsson", "given": "Anna-Lena", "initials": "AL", "orcid": "0000-0003-4332-2336", "affiliations": ["Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medicinal Biochemistry and Biophysics, Karolinska Institute, 17177, Solna, Sweden."], "links": {"self": {"href": "https://publications.scilifelab.se/researcher/6b014ef7ea0d461b8e2ddb87506b1252.json"}, "display": {"href": "https://publications.scilifelab.se/researcher/6b014ef7ea0d461b8e2ddb87506b1252"}}, "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": "412601f6ba354736b3238fd089ebe0cf", "links": {"self": {"href": "https://publications.scilifelab.se/publication/412601f6ba354736b3238fd089ebe0cf.json"}, "display": {"href": "https://publications.scilifelab.se/publication/412601f6ba354736b3238fd089ebe0cf"}}, "title": "In silico Druggability Assessment of the NUDIX Hydrolase Protein Family as a Workflow for Target Prioritization.", "authors": [{"family": "Michel", "given": "Maurice", "initials": "M"}, {"family": "Homan", "given": "Evert J", "initials": "EJ"}, {"family": "Wiita", "given": "Elis\u00e9e", "initials": "E"}, {"family": "Pedersen", "given": "Kia", "initials": "K"}, {"family": "Alml\u00f6f", "given": "Ingrid", "initials": "I"}, {"family": "Gustavsson", "given": "Anna-Lena", "initials": "AL", "orcid": "0000-0003-4332-2336", "researcher": {"href": "https://publications.scilifelab.se/researcher/6b014ef7ea0d461b8e2ddb87506b1252.json"}}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T"}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications.scilifelab.se/researcher/3d7256c271ea4adea404d4ff355f804e.json"}}, {"family": "Warpman Berglund", "given": "Ulrika", "initials": "U"}], "type": "journal article", "published": "2020-05-29", "journal": {"volume": "8", "issn": "2296-2646", "issue": null, "pages": "443", "title": "Front. Chem.", "issn-l": "2296-2646"}, "abstract": "Computational chemistry has now been widely accepted as a useful tool for shortening lead times in early drug discovery. When selecting new potential drug targets, it is important to assess the likelihood of finding suitable starting points for lead generation before pursuing costly high-throughput screening campaigns. By exploiting available high-resolution crystal structures, an in silico druggability assessment can facilitate the decision of whether, and in cases where several protein family members exist, which of these to pursue experimentally. Many of the algorithms and software suites commonly applied for in silico druggability assessment are complex, technically challenging and not always user-friendly. Here we applied the intuitive open access servers of DoGSite, FTMap and CryptoSite to comprehensively predict ligand binding pockets, druggability scores and conformationally active regions of the NUDIX protein family. In parallel we analyzed potential ligand binding sites, their druggability and pocket parameter using Schr\u00f6dinger's SiteMap. Then an in silico docking cascade of a subset of the ZINC FragNow library using the Glide docking program was performed to assess identified pockets for large-scale small-molecule binding. Subsequently, this initial dual ranking of druggable sites within the NUDIX protein family was benchmarked against experimental hit rates obtained both in-house and by others from traditional biochemical and fragment screening campaigns. The observed correlation suggests that the presented user-friendly workflow of a dual parallel in silico druggability assessment is applicable as a standalone method for decision on target prioritization and exclusion in future screening campaigns.", "doi": "10.3389/fchem.2020.00443", "pmid": "32548091", "labels": {"Protein Science Facility (PSF)": "Service", "Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [{"db": "pmc", "key": "PMC7274155"}], "notes": [], "created": "2020-06-02T11:23:46.275Z", "modified": "2025-10-17T13:04:28.304Z"}, {"entity": "publication", "iuid": "d18a2001ca2a484ea1267aaed4906d19", "links": {"self": {"href": "https://publications.scilifelab.se/publication/d18a2001ca2a484ea1267aaed4906d19.json"}, "display": {"href": "https://publications.scilifelab.se/publication/d18a2001ca2a484ea1267aaed4906d19"}}, "title": "Exploiting loss of heterozygosity for allele-selective colorectal cancer chemotherapy.", "authors": [{"family": "Rendo", "given": "Veronica", "initials": "V", "orcid": "0000-0002-2983-4020", "researcher": {"href": "https://publications.scilifelab.se/researcher/7f3fe17dd4464af585b16916a88c34b7.json"}}, {"family": "Stoimenov", "given": "Ivaylo", "initials": "I"}, {"family": "Mateus", "given": "Andr\u00e9", "initials": "A", "orcid": "0000-0001-6870-0677", "researcher": {"href": "https://publications.scilifelab.se/researcher/d79942eca68f4b2d8c2e72cf258f1213.json"}}, {"family": "Sj\u00f6berg", "given": "Elin", "initials": "E"}, {"family": "Svensson", "given": "Richard", "initials": "R"}, {"family": "Gustavsson", "given": "Anna-Lena", "initials": "AL", "orcid": "0000-0003-4332-2336", "researcher": {"href": "https://publications.scilifelab.se/researcher/6b014ef7ea0d461b8e2ddb87506b1252.json"}}, {"family": "Johansson", "given": "Lars", "initials": "L"}, {"family": "Ng", "given": "Adrian", "initials": "A"}, {"family": "O\u02bcBrien", "given": "Casey", "initials": "C", "orcid": "0000-0002-6572-4881", "researcher": {"href": "https://publications.scilifelab.se/researcher/5782c9d8ce674fe8ad55eba0d514da54.json"}}, {"family": "Giannakis", "given": "Marios", "initials": "M"}, {"family": "Artursson", "given": "Per", "initials": "P", "orcid": "0000-0002-3708-7395", "researcher": {"href": "https://publications.scilifelab.se/researcher/31575936c2714e1eb2f35c12df9a65a8.json"}}, {"family": "Nygren", "given": "Peter", "initials": "P"}, {"family": "Cheong", "given": "Ian", "initials": "I"}, {"family": "Sj\u00f6blom", "given": "Tobias", "initials": "T", "orcid": "0000-0001-6668-4140", "researcher": {"href": "https://publications.scilifelab.se/researcher/909f00a5bf6e465f9ff560b12bcd863a.json"}}], "type": "journal article", "published": "2020-03-11", "journal": {"title": "Nat Commun", "issn": "2041-1723", "issn-l": "2041-1723", "volume": "11", "issue": "1", "pages": "1308"}, "abstract": "Cancer chemotherapy targeting frequent loss of heterozygosity events is an attractive concept, since tumor cells may lack enzymatic activities present in normal constitutional cells. To find exploitable targets, we map prevalent genetic polymorphisms to protein structures and identify 45 nsSNVs (non-synonymous small nucleotide variations) near the catalytic sites of 17 enzymes frequently lost in cancer. For proof of concept, we select the gastrointestinal drug metabolic enzyme NAT2 at 8p22, which is frequently lost in colorectal cancers and has a common variant with 10-fold reduced activity. Small molecule screening results in a cytotoxic kinase inhibitor that impairs growth of cells with slow NAT2 and decreases the growth of tumors with slow NAT2 by half as compared to those with wild-type NAT2. Most of the patient-derived CRC cells expressing slow NAT2 also show sensitivity to 6-(4-aminophenyl)-N-(3,4,5-trimethoxyphenyl)pyrazin-2-amine (APA) treatment. These findings indicate that the therapeutic index of anti-cancer drugs can be altered by bystander mutations affecting drug metabolic genes.", "doi": "10.1038/s41467-020-15111-4", "pmid": "32161261", "labels": {"Bioinformatics Support for Computational Resources": "Service", "Chemical Biology Consortium Sweden": "Collaborative", "Drug Discovery and Development": "Service"}, "xrefs": [{"db": "pii", "key": "10.1038/s41467-020-15111-4"}, {"db": "pmc", "key": "PMC7066191"}], "notes": [], "created": "2020-03-17T11:11:47.766Z", "modified": "2025-10-17T13:05:08.058Z"}, {"entity": "publication", "iuid": "c148b498822c43108e78e3a56a3112bf", "links": {"self": {"href": "https://publications.scilifelab.se/publication/c148b498822c43108e78e3a56a3112bf.json"}, "display": {"href": "https://publications.scilifelab.se/publication/c148b498822c43108e78e3a56a3112bf"}}, "title": "Publisher Correction: A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage", "authors": [{"family": "Ladds", "given": "Marcus J G W", "initials": "MJGW"}, {"family": "van Leeuwen", "given": "Ingeborg M M", "initials": "IMM"}, {"family": "Drummond", "given": "Catherine J", "initials": "CJ"}, {"family": "Chu", "given": "Su", "initials": "S"}, {"family": "Healy", "given": "Alan R", "initials": "AR"}, {"family": "Popova", "given": "Gergana", "initials": "G"}, {"family": "Pastor Fern\u00e1ndez", "given": "Andr\u00e9s", "initials": "A"}, {"family": "Mollick", "given": "Tanzina", "initials": "T"}, {"family": "Darekar", "given": "Suhas", "initials": "S"}, {"family": "Sedimbi", "given": "Saikiran K", "initials": "SK"}, {"family": "Nekulova", "given": "Marta", "initials": "M"}, {"family": "Sachweh", "given": "Marijke C C", "initials": "MCC"}, {"family": "Campbell", "given": "Johanna", "initials": "J"}, {"family": "Higgins", "given": "Maureen", "initials": "M"}, {"family": "Tuck", "given": "Chloe", "initials": "C"}, {"family": "Popa", "given": "Mihaela", "initials": "M"}, {"family": "Safont", "given": "Mireia Mayoral", "initials": "MM"}, {"family": "Gelebart", "given": "Pascal", "initials": "P"}, {"family": "Fandalyuk", "given": "Zinayida", "initials": "Z"}, {"family": "Thompson", "given": "Alastair M", "initials": "AM"}, {"family": "Svensson", "given": "Richard", "initials": "R"}, {"family": "Gustavsson", "given": "Anna Lena", "initials": "AL", "orcid": "0000-0003-4332-2336", "researcher": {"href": "https://publications.scilifelab.se/researcher/6b014ef7ea0d461b8e2ddb87506b1252.json"}}, {"family": "Johansson", "given": "Lars", "initials": "L"}, {"family": "F\u00e4rneg\u00e5rdh", "given": "Katarina", "initials": "K"}, {"family": "Yngve", "given": "Ulrika", "initials": "U"}, {"family": "Saleh", "given": "Aljona", "initials": "A"}, {"family": "Haraldsson", "given": "Martin", "initials": "M"}, {"family": "D\u2019Hollander", "given": "Agathe C A", "initials": "ACA"}, {"family": "Franco", "given": "Marcela", "initials": "M"}, {"family": "Zhao", "given": "Yan", "initials": "Y"}, {"family": "H\u00e5kansson", "given": "Maria", "initials": "M"}, {"family": "Walse", "given": "Bj\u00f6rn", "initials": "B"}, {"family": "Larsson", "given": "Karin", "initials": "K"}, {"family": "Peat", "given": "Emma M", "initials": "EM"}, {"family": "Pelechano", "given": "Vicent", "initials": "V"}, {"family": "Lunec", "given": "John", "initials": "J"}, {"family": "Vojtesek", "given": "Borivoj", "initials": "B"}, {"family": "Carmena", "given": "Mar", "initials": "M"}, {"family": "Earnshaw", "given": "William C", "initials": "WC"}, {"family": "McCarthy", "given": "Anna R", "initials": "AR"}, {"family": "Westwood", "given": "Nicholas J", "initials": "NJ"}, {"family": "Arsenian-Henriksson", "given": "Marie", "initials": "M"}, {"family": "Lane", "given": "David P", "initials": "DP"}, {"family": "Bhatia", "given": "Ravi", "initials": "R"}, {"family": "McCormack", "given": "Emmet", "initials": "E"}, {"family": "La\u00edn", "given": "Sonia", "initials": "S"}], "type": "journal-article", "published": "2018-12-00", "journal": {"volume": "9", "issn": "2041-1723", "issue": "1", "pages": null, "title": "Nat Commun", "issn-l": "2041-1723"}, "abstract": "The original PDF version of this Article listed the authors as \"Marcus J.G.W. Ladds,\" where it should have read \"Marcus J. G. W. Ladds, Ingeborg M. M. van Leeuwen, Catherine J. Drummond et al.\n            #\".Also in the PDF version, it was incorrectly stated that \"Correspondence and requests for materials should be addressed to S. L\u00edn.\", instead of the correct \"Correspondence and requests for materials should be addressed to S. La\u00edn.\"This has been corrected in the PDF version of the Article. The HTML version was correct from the time of publication.", "doi": "10.1038/s41467-018-04198-5", "pmid": "29789663", "labels": {"Bioinformatics Support for Computational Resources": "Service", "Drug Discovery and Development": "Service"}, "xrefs": [], "notes": [], "created": "2018-10-22T13:17:34.442Z", "modified": "2025-10-17T13:05:08.314Z"}, {"entity": "publication", "iuid": "e560c225188b458bba0104756c13d202", "links": {"self": {"href": "https://publications.scilifelab.se/publication/e560c225188b458bba0104756c13d202.json"}, "display": {"href": "https://publications.scilifelab.se/publication/e560c225188b458bba0104756c13d202"}}, "title": "Identification of inhibitors of Tartrate-resistant acid phosphatase (TRAP/ACP5) activity by small-molecule screening.", "authors": [{"family": "Reithmeier", "given": "Anja", "initials": "A", "orcid": "0000-0003-4555-9636", "researcher": {"href": "https://publications.scilifelab.se/researcher/17c47f54859f4d2ea1b153a38cb877ad.json"}}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T"}, {"family": "Haraldsson", "given": "Martin", "initials": "M"}, {"family": "Frank", "given": "Martin", "initials": "M"}, {"family": "Ek-Rylander", "given": "Barbro", "initials": "B"}, {"family": "Nyholm", "given": "Per-Georg", "initials": "PG"}, {"family": "Gustavsson", "given": "Anna-Lena", "initials": "AL", "orcid": "0000-0003-4332-2336", "researcher": {"href": "https://publications.scilifelab.se/researcher/6b014ef7ea0d461b8e2ddb87506b1252.json"}}, {"family": "Andersson", "given": "G\u00f6ran", "initials": "G"}], "type": "journal article", "published": "2018-07-00", "journal": {"volume": "92", "issn": "1747-0285", "issue": "1", "pages": "1255-1271", "title": "Chem Biol Drug Des", "issn-l": "1747-0277"}, "abstract": "Tartrate-resistant acid phosphatase (TRAP/ACP5) occurs as two isoforms-TRAP 5a with low enzymatic activity due to a loop interacting with the active site and the more active TRAP isoform 5b generated upon proteolytic cleavage of this loop. TRAP has been implicated in several diseases, including cancer. Thus, this study set out to identify small-molecule inhibitors of TRAP activity. A microplate-based enzymatic assay for TRAP 5b was applied in a screen of 30,315 compounds, resulting in the identification of 90 primary hits. After removal of promiscuous compounds, unwanted groups, and false positives by orthogonal assays and three-concentration validation, the properties of 52 compounds were further investigated to better understand their mechanism of action. Full-concentration-response curves for these compounds were established under different enzyme concentrations and (pre)incubation times to remove compounds with inconsistent results and low potencies. Full-concentration-response curves were also performed for both isoforms, to examine isoform prevalence. Filtering led to six prioritized compounds, representing different clusters. One of these, CBK289001 or (6S)-6-[3-(2H-1,3-benzodioxol-5-yl)-1,2,4-oxadiazol-5-yl]-N-(propan-2-yl)-1H,4H,5H,6H,7H-imidazo[4,5-c]pyridine-5-carboxamide, demonstrated efficacy in a migration assay and IC50 values from 4 to 125 \u03bcm. Molecular docking studies and analog testing were performed around CBK289001 to provide openings for further improvement toward more potent blockers of TRAP activity.", "doi": "10.1111/cbdd.13187", "pmid": "29500863", "labels": {"Bioinformatics Support for Computational Resources": "Service", "Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [], "notes": [], "created": "2018-10-15T08:49:43.798Z", "modified": "2025-10-17T13:04:28.900Z"}, {"entity": "publication", "iuid": "906aeab4b0d1446586bd69fdcaf47fce", "links": {"self": {"href": "https://publications.scilifelab.se/publication/906aeab4b0d1446586bd69fdcaf47fce.json"}, "display": {"href": "https://publications.scilifelab.se/publication/906aeab4b0d1446586bd69fdcaf47fce"}}, "title": "A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage.", "authors": [{"family": "Ladds", "given": "Marcus J G W", "initials": "MJGW"}, {"family": "van Leeuwen", "given": "Ingeborg M M", "initials": "IMM"}, {"family": "Drummond", "given": "Catherine J", "initials": "CJ"}, {"family": "Chu", "given": "Su", "initials": "S"}, {"family": "Healy", "given": "Alan R", "initials": "AR"}, {"family": "Popova", "given": "Gergana", "initials": "G"}, {"family": "Pastor Fern\u00e1ndez", "given": "Andr\u00e9s", "initials": "A"}, {"family": "Mollick", "given": "Tanzina", "initials": "T"}, {"family": "Darekar", "given": "Suhas", "initials": "S"}, {"family": "Sedimbi", "given": "Saikiran K", "initials": "SK"}, {"family": "Nekulova", "given": "Marta", "initials": "M"}, {"family": "Sachweh", "given": "Marijke C C", "initials": "MCC"}, {"family": "Campbell", "given": "Johanna", "initials": "J"}, {"family": "Higgins", "given": "Maureen", "initials": "M"}, {"family": "Tuck", "given": "Chloe", "initials": "C"}, {"family": "Popa", "given": "Mihaela", "initials": "M"}, {"family": "Safont", "given": "Mireia Mayoral", "initials": "MM"}, {"family": "Gelebart", "given": "Pascal", "initials": "P"}, {"family": "Fandalyuk", "given": "Zinayida", "initials": "Z"}, {"family": "Thompson", "given": "Alastair M", "initials": "AM"}, {"family": "Svensson", "given": "Richard", "initials": "R"}, {"family": "Gustavsson", "given": "Anna-Lena", "initials": "AL", "orcid": "0000-0003-4332-2336", "researcher": {"href": "https://publications.scilifelab.se/researcher/6b014ef7ea0d461b8e2ddb87506b1252.json"}}, {"family": "Johansson", "given": "Lars", "initials": "L"}, {"family": "F\u00e4rneg\u00e5rdh", "given": "Katarina", "initials": "K"}, {"family": "Yngve", "given": "Ulrika", "initials": "U"}, {"family": "Saleh", "given": "Aljona", "initials": "A"}, {"family": "Haraldsson", "given": "Martin", "initials": "M"}, {"family": "D'Hollander", "given": "Agathe C A", "initials": "ACA"}, {"family": "Franco", "given": "Marcela", "initials": "M"}, {"family": "Zhao", "given": "Yan", "initials": "Y"}, {"family": "H\u00e5kansson", "given": "Maria", "initials": "M"}, {"family": "Walse", "given": "Bj\u00f6rn", "initials": "B"}, {"family": "Larsson", "given": "Karin", "initials": "K", "orcid": "0000-0002-6403-2736", "researcher": {"href": "https://publications.scilifelab.se/researcher/c015846a43c54cd1a1a2b52e6caa1740.json"}}, {"family": "Peat", "given": "Emma M", "initials": "EM"}, {"family": "Pelechano", "given": "Vicent", "initials": "V"}, {"family": "Lunec", "given": "John", "initials": "J"}, {"family": "Vojtesek", "given": "Borivoj", "initials": "B"}, {"family": "Carmena", "given": "Mar", "initials": "M", "orcid": "0000-0002-2352-1066", "researcher": {"href": "https://publications.scilifelab.se/researcher/bd5d0ef8fa3947bfbe59606a74da4eaa.json"}}, {"family": "Earnshaw", "given": "William C", "initials": "WC"}, {"family": "McCarthy", "given": "Anna R", "initials": "AR"}, {"family": "Westwood", "given": "Nicholas J", "initials": "NJ", "orcid": "0000-0003-0630-0138", "researcher": {"href": "https://publications.scilifelab.se/researcher/f6d109f545d5477e9686475989c8ef5a.json"}}, {"family": "Arsenian-Henriksson", "given": "Marie", "initials": "M"}, {"family": "Lane", "given": "David P", "initials": "DP"}, {"family": "Bhatia", "given": "Ravi", "initials": "R"}, {"family": "McCormack", "given": "Emmet", "initials": "E"}, {"family": "La\u00edn", "given": "Sonia", "initials": "S"}], "type": "journal article", "published": "2018-03-16", "journal": {"volume": "9", "issn": "2041-1723", "issue": "1", "pages": "1107", "title": "Nat Commun", "issn-l": "2041-1723"}, "abstract": "The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.", "doi": "10.1038/s41467-018-03441-3", "pmid": "29549331", "labels": {"Protein Science Facility (PSF)": "Service", "Bioinformatics Support for Computational Resources": "Service", "Chemical Biology Consortium Sweden": "Collaborative", "Drug Discovery and Development": "Collaborative"}, "xrefs": [{"db": "pii", "key": "10.1038/s41467-018-03441-3"}, {"db": "pmc", "key": "PMC5856786"}], "notes": [], "created": "2018-04-09T08:28:05.800Z", "modified": "2025-10-17T13:05:08.481Z"}, {"entity": "publication", "iuid": "56260de3ac3b4598909dc39816e56618", "links": {"self": {"href": "https://publications.scilifelab.se/publication/56260de3ac3b4598909dc39816e56618.json"}, "display": {"href": "https://publications.scilifelab.se/publication/56260de3ac3b4598909dc39816e56618"}}, "title": "Drug Target Commons: A Community Effort to Build a Consensus Knowledge Base for Drug-Target Interactions.", "authors": [{"family": "Tang", "given": "Jing", "initials": "J"}, {"family": "Tanoli", "given": "Zia-Ur-Rehman", "initials": "ZU"}, {"family": "Ravikumar", "given": "Balaguru", "initials": "B"}, {"family": "Alam", "given": "Zaid", "initials": "Z"}, {"family": "Rebane", "given": "Anni", "initials": "A"}, {"family": "V\u00e4h\u00e4-Koskela", "given": "Markus", "initials": "M"}, {"family": "Peddinti", "given": "Gopal", "initials": "G"}, {"family": "van Adrichem", "given": "Arjan J", "initials": "AJ"}, {"family": "Wakkinen", "given": "Janica", "initials": "J"}, {"family": "Jaiswal", "given": "Alok", "initials": "A"}, {"family": "Karjalainen", "given": "Ella", "initials": "E"}, {"family": "Gautam", "given": "Prson", "initials": "P"}, {"family": "He", "given": "Liye", "initials": "L"}, {"family": "Parri", "given": "Elina", "initials": "E"}, {"family": "Khan", "given": "Suleiman", "initials": "S"}, {"family": "Gupta", "given": "Abhishekh", "initials": "A"}, {"family": "Ali", "given": "Mehreen", "initials": "M"}, {"family": "Yetukuri", "given": "Laxman", "initials": "L"}, {"family": "Gustavsson", "given": "Anna-Lena", "initials": "AL", "orcid": "0000-0003-4332-2336", "researcher": {"href": "https://publications.scilifelab.se/researcher/6b014ef7ea0d461b8e2ddb87506b1252.json"}}, {"family": "Seashore-Ludlow", "given": "Brinton", "initials": "B"}, {"family": "Hersey", "given": "Anne", "initials": "A"}, {"family": "Leach", "given": "Andrew R", "initials": "AR"}, {"family": "Overington", "given": "John P", "initials": "JP"}, {"family": "Repasky", "given": "Gretchen", "initials": "G"}, {"family": "Wennerberg", "given": "Krister", "initials": "K"}, {"family": "Aittokallio", "given": "Tero", "initials": "T"}], "type": "journal article", "published": "2018-02-15", "journal": {"volume": "25", "issn": "2451-9448", "issue": "2", "pages": "224-229.e2", "title": "Cell Chem Biol", "issn-l": null}, "abstract": "Knowledge of the full target space of bioactive substances, approved and investigational drugs as well as chemical probes, provides important insights into therapeutic potential and possible adverse effects. The existing compound-target bioactivity data resources are often incomparable due to non-standardized and heterogeneous assay types and variability in endpoint measurements. To extract higher value from the existing and future compound target-profiling data, we implemented an open-data web platform, named Drug Target Commons (DTC), which features tools for crowd-sourced compound-target bioactivity data annotation, standardization, curation, and intra-resource integration. We demonstrate the unique value of DTC with several examples related to both drug discovery and drug repurposing applications and invite researchers to join this community effort to increase the reuse and extension of compound bioactivity data.", "doi": "10.1016/j.chembiol.2017.11.009", "pmid": "29276046", "labels": {"Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [{"db": "pii", "key": "S2451-9456(17)30426-9"}, {"db": "pmc", "key": "PMC5814751"}], "notes": [], "created": "2018-01-17T12:35:58.545Z", "modified": "2025-10-17T13:04:28.972Z"}, {"entity": "publication", "iuid": "83a7f53f82784bc18e60e7b0bf1ea3f9", "links": {"self": {"href": "https://publications.scilifelab.se/publication/83a7f53f82784bc18e60e7b0bf1ea3f9.json"}, "display": {"href": "https://publications.scilifelab.se/publication/83a7f53f82784bc18e60e7b0bf1ea3f9"}}, "title": "A Drosophila female pheromone elicits species-specific long-range attraction via an olfactory channel with dual specificity for sex and food.", "authors": [{"family": "Lebreton", "given": "Sebastien", "initials": "S"}, {"family": "Borrero-Echeverry", "given": "Felipe", "initials": "F"}, {"family": "Gonzalez", "given": "Francisco", "initials": "F"}, {"family": "Solum", "given": "Marit", "initials": "M"}, {"family": "Wallin", "given": "Erika A", "initials": "EA"}, {"family": "Hedenstr\u00f6m", "given": "Erik", "initials": "E"}, {"family": "Hansson", "given": "Bill S", "initials": "BS"}, {"family": "Gustavsson", "given": "Anna-Lena", "initials": "AL", "orcid": "0000-0003-4332-2336", "researcher": {"href": "https://publications.scilifelab.se/researcher/6b014ef7ea0d461b8e2ddb87506b1252.json"}}, {"family": "Bengtsson", "given": "Marie", "initials": "M"}, {"family": "Birgersson", "given": "G\u00f6ran", "initials": "G"}, {"family": "Walker", "given": "William B", "initials": "WB"}, {"family": "Dweck", "given": "Hany K M", "initials": "HKM"}, {"family": "Becher", "given": "Paul G", "initials": "PG"}, {"family": "Witzgall", "given": "Peter", "initials": "P", "orcid": "0000-0002-4697-3380", "researcher": {"href": "https://publications.scilifelab.se/researcher/548d4ff93a3f488e8133e5f7b1f79097.json"}}], "type": "journal article", "published": "2017-09-29", "journal": {"volume": "15", "issn": "1741-7007", "issue": "1", "pages": "88", "title": "BMC Biol.", "issn-l": "1741-7007"}, "abstract": "Mate finding and recognition in animals evolves during niche adaptation and involves social signals and habitat cues. Drosophila melanogaster and related species are known to be attracted to fermenting fruit for feeding and egg-laying, which poses the question of whether species-specific fly odours contribute to long-range premating communication.\n\nWe have discovered an olfactory channel in D. melanogaster with a dual affinity to sex and food odorants. Female flies release a pheromone, (Z)-4-undecenal (Z4-11Al), that elicits flight attraction in both sexes. Its biosynthetic precursor is the cuticular hydrocarbon (Z,Z)-7,11-heptacosadiene (7,11-HD), which is known to afford reproductive isolation between the sibling species D. melanogaster and D. simulans during courtship. Twin olfactory receptors, Or69aB and Or69aA, are tuned to Z4-11Al and food odorants, respectively. They are co-expressed in the same olfactory sensory neurons, and feed into a neural circuit mediating species-specific, long-range communication; however, the close relative D. simulans, which shares food resources with D. melanogaster, does not respond to Z4-11Al.\n\nThe Or69aA and Or69aB isoforms have adopted dual olfactory traits. The underlying gene yields a collaboration between natural and sexual selection, which has the potential to drive speciation.", "doi": "10.1186/s12915-017-0427-x", "pmid": "28962619", "labels": {"Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [{"db": "pii", "key": "10.1186/s12915-017-0427-x"}, {"db": "pmc", "key": "PMC5622430"}, {"db": "Dryad", "key": "10.5061/dryad.v54v8"}], "notes": [], "created": "2017-10-31T13:35:54.413Z", "modified": "2025-10-17T13:04:29.117Z"}, {"entity": "publication", "iuid": "64b356ba093a4bf180f042a619c896a0", "links": {"self": {"href": "https://publications.scilifelab.se/publication/64b356ba093a4bf180f042a619c896a0.json"}, "display": {"href": "https://publications.scilifelab.se/publication/64b356ba093a4bf180f042a619c896a0"}}, "title": "High-affinity recognition of the human C-reactive protein independent of phosphocholine.", "authors": [{"family": "Yang", "given": "Jie", "initials": "J"}, {"family": "Gustavsson", "given": "Anna-Lena", "initials": "AL", "orcid": "0000-0003-4332-2336", "researcher": {"href": "https://publications.scilifelab.se/researcher/6b014ef7ea0d461b8e2ddb87506b1252.json"}}, {"family": "Haraldsson", "given": "Martin", "initials": "M"}, {"family": "Karlsson", "given": "G\u00f6ran", "initials": "G", "orcid": "0000-0002-1821-4715", "researcher": {"href": "https://publications.scilifelab.se/researcher/2c6463abd05b415696c52be577ca2be6.json"}}, {"family": "Norberg", "given": "Thomas", "initials": "T", "orcid": "0000-0002-0675-7675", "researcher": {"href": "https://publications.scilifelab.se/researcher/a85dcf5837e641a4a844401b54dae2d9.json"}}, {"family": "Baltzer", "given": "Lars", "initials": "L", "orcid": "0000-0001-5807-2726", "researcher": {"href": "https://publications.scilifelab.se/researcher/ca711c9ac6fd43e4baf6e95886c85774.json"}}], "type": "journal article", "published": "2017-05-31", "journal": {"volume": "15", "issn": "1477-0539", "issue": "21", "pages": "4644-4654", "title": "Org. Biomol. Chem.", "issn-l": "1477-0520"}, "abstract": "A high-affinity polypeptide conjugate 4-C25L22-DQ, has been developed for the molecular recognition of the human C-reactive protein, CRP, a well-known inflammation biomarker. CRP is one of the most frequently quantified targets in diagnostic applications and a target in drug development. With the exception of antibodies, most molecular constructs take advantage of the known affinity for CRP of phosphocholine that depends on Ca2+ for its ability to bind. 4-C25L22-DQ which is unrelated to phosphocholine binds in the absence of Ca2+ with a dissociation constant of 760 nM, an order of magnitude lower than that of phosphocholine, the KD of which is 5 \u03bcM. The small organic molecule 2-oxo-1,2-dihydroquinoline-8-carboxylic acid (DQ) was designed based on the structural similarities between three hits from a set of compounds selected from a building block collection and evaluated with regards to affinity for CRP by NMR spectroscopy. 4-C25L22-DQ was shown in a competition experiment to bind CRP three orders of magnitude more strongly than DQ itself, and in a pull-down experiment 4-C25L22-DQ was shown to extract CRP from human serum. The development of a robust and phosphocholine-independent recognition element provides unprecedented opportunities in bioanalytical applications in vivo and in vitro under conditions where the concentration of Ca2+ ions is low, or where Ca2+ binding agents such as EDTA or heparin are needed to prevent blood coagulation. The identification from a compound library of a small organic molecule and its conjugation to a small set of polypeptides, none of which were previously known to bind CRP, illustrates a convenient and general route to selective high-affinity binders for proteins with dissociation constants in the \u03bcM to nM range for which no small molecule ligands are known.", "doi": "10.1039/c7ob00684e", "pmid": "28513744", "labels": {"Swedish NMR Centre": "Service", "Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [], "notes": [], "created": "2017-10-20T15:12:12.567Z", "modified": "2025-10-17T13:04:29.262Z"}, {"entity": "publication", "iuid": "a54451a7ba4f4e42b547db6d29ef15fa", "links": {"self": {"href": "https://publications.scilifelab.se/publication/a54451a7ba4f4e42b547db6d29ef15fa.json"}, "display": {"href": "https://publications.scilifelab.se/publication/a54451a7ba4f4e42b547db6d29ef15fa"}}, "title": "Corrigendum: MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool.", "authors": [{"family": "Gad", "given": "Helge", "initials": "H"}, {"family": "Koolmeister", "given": "Tobias", "initials": "T"}, {"family": "Jemth", "given": "Ann-Sofie", "initials": "AS"}, {"family": "Eshtad", "given": "Saeed", "initials": "S"}, {"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"}, {"family": "Einarsdottir", "given": "Berglind Osk", "initials": "BO"}, {"family": "Saleh", "given": "Aljona", "initials": "A"}, {"family": "G\u00f6kt\u00fcrk", "given": "Camilla", "initials": "C"}, {"family": "Baranczewski", "given": "Pawel", "initials": "P"}, {"family": "Svensson", "given": "Richard", "initials": "R"}, {"family": "Berntsson", "given": "Ronnie P-A", "initials": "RP"}, {"family": "Gustafsson", "given": "Robert", "initials": "R"}, {"family": "Str\u00f6mberg", "given": "Kia", "initials": "K"}, {"family": "Sanjiv", "given": "Kumar", "initials": "K"}, {"family": "Jacques-Cordonnier", "given": "Marie-Caroline", "initials": "MC"}, {"family": "Desroses", "given": "Matthieu", "initials": "M"}, {"family": "Gustavsson", "given": "Anna-Lena", "initials": "AL", "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"}, {"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"}, {"family": "H\u00f6glund", "given": "Andreas", "initials": "A"}, {"family": "Hagenkort", "given": "Anna", "initials": "A"}, {"family": "Pham", "given": "Therese", "initials": "T"}, {"family": "Altun", "given": "Mikael", "initials": "M"}, {"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"}, {"family": "Djureinovic", "given": "Tatjana", "initials": "T"}, {"family": "Carreras Puigvert", "given": "Jordi", "initials": "J"}, {"family": "H\u00e4ggblad", "given": "Maria", "initials": "M"}, {"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": "Jenmalm Jensen", "given": "Annika", "initials": "A"}, {"family": "Artursson", "given": "Per", "initials": "P"}, {"family": "Nilsson", "given": "Jonas A", "initials": "JA"}, {"family": "Stenmark", "given": "P\u00e5l", "initials": "P"}, {"family": "Scobie", "given": "Martin", "initials": "M"}, {"family": "Ulrika Warpman Berglund &Thomas Helleday", "given": "", "initials": ""}], "type": "journal article", "published": "2017-04-26", "journal": {"volume": "544", "issn": "1476-4687", "issue": "7651", "pages": "508", "title": "Nature", "issn-l": "0028-0836"}, "abstract": null, "doi": "10.1038/nature22083", "pmid": "28447629", "labels": {"Drug Discovery and Development": "Service"}, "xrefs": [{"db": "pii", "key": "nature22083"}], "notes": "Biochemical and Cellular Screening", "created": "2017-11-01T09:58:56.990Z", "modified": "2025-10-17T13:05:08.951Z"}, {"entity": "publication", "iuid": "e7393cb4fb5c445394eba1f7b1b6f31f", "links": {"self": {"href": "https://publications.scilifelab.se/publication/e7393cb4fb5c445394eba1f7b1b6f31f.json"}, "display": {"href": "https://publications.scilifelab.se/publication/e7393cb4fb5c445394eba1f7b1b6f31f"}}, "title": "dUTPase inhibition augments replication defects of 5-Fluorouracil.", "authors": [{"family": "Hagenkort", "given": "Anna", "initials": "A"}, {"family": "Paulin", "given": "Cynthia B J", "initials": "CBJ"}, {"family": "Desroses", "given": "Matthieu", "initials": "M"}, {"family": "Sarno", "given": "Antonio", "initials": "A"}, {"family": "Wiita", "given": "Elis\u00e9e", "initials": "E"}, {"family": "Mortusewicz", "given": "Oliver", "initials": "O"}, {"family": "Koolmeister", "given": "Tobias", "initials": "T"}, {"family": "Loseva", "given": "Olga", "initials": "O"}, {"family": "Jemth", "given": "Ann-Sofie", "initials": "A"}, {"family": "Alml\u00f6f", "given": "Ingrid", "initials": "I"}, {"family": "Homan", "given": "Evert", "initials": "E"}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T"}, {"family": "Gustavsson", "given": "Anna-Lena", "initials": "A", "orcid": "0000-0003-4332-2336", "researcher": {"href": "https://publications.scilifelab.se/researcher/6b014ef7ea0d461b8e2ddb87506b1252.json"}}, {"family": "Scobie", "given": "Martin", "initials": "M"}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications.scilifelab.se/researcher/3d7256c271ea4adea404d4ff355f804e.json"}}], "type": "journal article", "published": "2017-04-04", "journal": {"volume": "8", "issn": "1949-2553", "issue": "14", "pages": "23713-23726", "title": "Oncotarget", "issn-l": "1949-2553"}, "abstract": "The antimetabolite 5-Fluorouracil (5-FU) is used in the treatment of various forms of cancer and has a complex mode of action. Despite 6 decades in clinical application the contribution of 5-FdUTP and dUTP [(5-F)dUTP] and 5-FUTP misincorporation into DNA and RNA respectively, for 5-FU-induced toxicity is still under debate.This study investigates DNA replication defects induced by 5-FU treatment and how (5-F)dUTP accumulation contributes to this effect. We reveal that 5-FU treatment leads to extensive problems in DNA replication fork progression, causing accumulation of cells in S-phase, DNA damage and ultimately cell death. Interestingly, these effects can be reinforced by either depletion or inhibition of the deoxyuridine triphosphatase (dUTPase, also known as DUT), highlighting the importance of (5-F)dUTP accumulation for cytotoxicity.With this study, we not only extend the current understanding of the mechanism of action of 5-FU, but also contribute to the characterization of dUTPase inhibitors. We demonstrate that pharmacological inhibition of dUTPase is a promising approach that may improve the efficacy of 5-FU treatment in the clinic.", "doi": "10.18632/oncotarget.15785", "pmid": "28423595", "labels": {"Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [{"db": "pii", "key": "15785"}, {"db": "pmc", "key": "PMC5410339"}], "notes": [], "created": "2017-10-20T15:11:22.720Z", "modified": "2025-10-17T13:04:29.288Z"}, {"entity": "publication", "iuid": "b672cfafccdb450093604f54c0d0dc48", "links": {"self": {"href": "https://publications.scilifelab.se/publication/b672cfafccdb450093604f54c0d0dc48.json"}, "display": {"href": "https://publications.scilifelab.se/publication/b672cfafccdb450093604f54c0d0dc48"}}, "title": "Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses.", "authors": [{"family": "Niklasson", "given": "Mia", "initials": "M"}, {"family": "Maddalo", "given": "Gianluca", "initials": "G"}, {"family": "Sramkova", "given": "Zuzana", "initials": "Z"}, {"family": "Mutlu", "given": "Ercan", "initials": "E"}, {"family": "Wee", "given": "Shimei", "initials": "S"}, {"family": "Sekyrova", "given": "Petra", "initials": "P"}, {"family": "Schmidt", "given": "Linn\u00e9a", "initials": "L"}, {"family": "Fritz", "given": "Nicolas", "initials": "N"}, {"family": "Dehnisch", "given": "Ivar", "initials": "I"}, {"family": "Kyriatzis", "given": "Gregorios", "initials": "G"}, {"family": "Krafcikova", "given": "Michaela", "initials": "M"}, {"family": "Carson", "given": "Brittany B", "initials": "BB"}, {"family": "Feenstra", "given": "Jennifer M", "initials": "JM"}, {"family": "Marinescu", "given": "Voichita D", "initials": "VD"}, {"family": "Segerman", "given": "Anna", "initials": "A"}, {"family": "Haraldsson", "given": "Martin", "initials": "M"}, {"family": "Gustavsson", "given": "Anna-Lena", "initials": "AL", "orcid": "0000-0003-4332-2336", "researcher": {"href": "https://publications.scilifelab.se/researcher/6b014ef7ea0d461b8e2ddb87506b1252.json"}}, {"family": "Hammarstr\u00f6m", "given": "Lars G J", "initials": "LG"}, {"family": "Jenmalm Jensen", "given": "Annika", "initials": "A"}, {"family": "Uhrbom", "given": "Lene", "initials": "L"}, {"family": "Altelaar", "given": "A F Maarten", "initials": "AF"}, {"family": "Linnarsson", "given": "Sten", "initials": "S"}, {"family": "Uhl\u00e9n", "given": "Per", "initials": "P"}, {"family": "Trantirek", "given": "Lukas", "initials": "L"}, {"family": "Vincent", "given": "C Theresa", "initials": "CT"}, {"family": "Nelander", "given": "Sven", "initials": "S"}, {"family": "Enger", "given": "Per \u00d8yvind", "initials": "P\u00d8"}, {"family": "And\u00e4ng", "given": "Michael", "initials": "M"}], "type": "journal article", "published": "2017-04-01", "journal": {"volume": "77", "issn": "1538-7445", "issue": "7", "pages": "1741-1752", "title": "Cancer Res.", "issn-l": "0008-5472"}, "abstract": "Glioma-initiating cells (GIC) are considered the underlying cause of recurrences of aggressive glioblastomas, replenishing the tumor population and undermining the efficacy of conventional chemotherapy. Here we report the discovery that inhibiting T-type voltage-gated Ca2+ and KCa channels can effectively induce selective cell death of GIC and increase host survival in an orthotopic mouse model of human glioma. At present, the precise cellular pathways affected by the drugs affecting these channels are unknown. However, using cell-based assays and integrated proteomics, phosphoproteomics, and transcriptomics analyses, we identified the downstream signaling events these drugs affect. Changes in plasma membrane depolarization and elevated intracellular Na+, which compromised Na+-dependent nutrient transport, were documented. Deficits in nutrient deficit acted in turn to trigger the unfolded protein response and the amino acid response, leading ultimately to nutrient starvation and GIC cell death. Our results suggest new therapeutic targets to attack aggressive gliomas. Cancer Res; 77(7); 1741-52. \u00a92017 AACR.", "doi": "10.1158/0008-5472.CAN-16-2274", "pmid": "28087597", "labels": {"Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [{"db": "pii", "key": "0008-5472.CAN-16-2274"}], "notes": [], "created": "2017-10-20T15:10:26.209Z", "modified": "2025-10-17T13:04:29.305Z"}, {"entity": "publication", "iuid": "cebeb1e4688745acb06f176d496e4581", "links": {"self": {"href": "https://publications.scilifelab.se/publication/cebeb1e4688745acb06f176d496e4581.json"}, "display": {"href": "https://publications.scilifelab.se/publication/cebeb1e4688745acb06f176d496e4581"}}, "title": "Inhibitors of the Cysteine Synthase CysM with Antibacterial Potency against Dormant Mycobacterium tuberculosis.", "authors": [{"family": "Brunner", "given": "Katharina", "initials": "K"}, {"family": "Maric", "given": "Selma", "initials": "S"}, {"family": "Reshma", "given": "Rudraraju Srilakshmi", "initials": "RS"}, {"family": "Almqvist", "given": "Helena", "initials": "H"}, {"family": "Seashore-Ludlow", "given": "Brinton", "initials": "B"}, {"family": "Gustavsson", "given": "Anna-Lena", "initials": "AL", "orcid": "0000-0003-4332-2336", "researcher": {"href": "https://publications.scilifelab.se/researcher/6b014ef7ea0d461b8e2ddb87506b1252.json"}}, {"family": "Poyraz", "given": "\u00d6mer", "initials": "\u00d6"}, {"family": "Yogeeswari", "given": "Perumal", "initials": "P"}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T"}, {"family": "Vallin", "given": "Michaela", "initials": "M"}, {"family": "Sriram", "given": "Dharmarajan", "initials": "D"}, {"family": "Schnell", "given": "Robert", "initials": "R"}, {"family": "Schneider", "given": "Gunter", "initials": "G"}], "type": "journal article", "published": "2016-07-28", "journal": {"volume": "59", "issn": "1520-4804", "issue": "14", "pages": "6848-6859", "title": "J. Med. Chem.", "issn-l": "0022-2623"}, "abstract": "Cysteine is an important amino acid in the redox defense of Mycobacterium tuberculosis, primarily as a building block of mycothiol. Genetic studies have implicated de novo cysteine biosynthesis in pathogen survival in infected macrophages, in particular for persistent M. tuberculosis. Here, we report on the identification and characterization of potent inhibitors of CysM, a critical enzyme in cysteine biosynthesis during dormancy. A screening campaign of 17\u202f312 compounds identified ligands that bind to the active site with micromolar affinity. These were characterized in terms of their inhibitory potencies and structure-activity relationships through hit expansion guided by three-dimensional structures of enzyme-inhibitor complexes. The top compound binds to CysM with 300 nM affinity and displays selectivity over the mycobacterial homologues CysK1 and CysK2. Notably, two inhibitors show significant potency in a nutrient-starvation model of dormancy of Mycobacterium tuberculosis, with little or no cytotoxicity toward mammalian cells.", "doi": "10.1021/acs.jmedchem.6b00674", "pmid": "27379713", "labels": {"Protein Science Facility (PSF)": "Service", "Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [], "notes": "Laboratories for Chemical Biology at Karolinska Institutet (LCBKI)", "created": "2017-05-03T12:59:29.713Z", "modified": "2025-10-17T13:04:29.482Z"}, {"entity": "publication", "iuid": "91ccc301bead4bd8961955b65f248dc8", "links": {"self": {"href": "https://publications.scilifelab.se/publication/91ccc301bead4bd8961955b65f248dc8.json"}, "display": {"href": "https://publications.scilifelab.se/publication/91ccc301bead4bd8961955b65f248dc8"}}, "title": "Design of a general-purpose European compound screening library for EU-OPENSCREEN.", "authors": [{"family": "Horvath", "given": "Dragos", "initials": "D"}, {"family": "Lisurek", "given": "Michael", "initials": "M"}, {"family": "Rupp", "given": "Bernd", "initials": "B"}, {"family": "K\u00fchne", "given": "Ronald", "initials": "R"}, {"family": "Specker", "given": "Edgar", "initials": "E"}, {"family": "von Kries", "given": "Jens", "initials": "J"}, {"family": "Rognan", "given": "Didier", "initials": "D"}, {"family": "Andersson", "given": "C David", "initials": "CD"}, {"family": "Almqvist", "given": "Fredrik", "initials": "F"}, {"family": "Elofsson", "given": "Mikael", "initials": "M"}, {"family": "Enqvist", "given": "Per-Anders", "initials": "PA"}, {"family": "Gustavsson", "given": "Anna-Lena", "initials": "AL", "orcid": "0000-0003-4332-2336", "researcher": {"href": "https://publications.scilifelab.se/researcher/6b014ef7ea0d461b8e2ddb87506b1252.json"}}, {"family": "Remez", "given": "Nikita", "initials": "N"}, {"family": "Mestres", "given": "Jordi", "initials": "J"}, {"family": "Marcou", "given": "Gilles", "initials": "G"}, {"family": "Varnek", "given": "Alexander", "initials": "A"}, {"family": "Hibert", "given": "Marcel", "initials": "M"}, {"family": "Quintana", "given": "Jordi", "initials": "J"}, {"family": "Frank", "given": "Ronald", "initials": "R"}], "type": "journal article", "published": "2014-10-00", "journal": {"volume": "9", "issn": "1860-7187", "issue": "10", "pages": "2309-2326", "title": "ChemMedChem", "issn-l": "1860-7179"}, "abstract": "This work describes a collaborative effort to define and apply a protocol for the rational selection of a general-purpose screening library, to be used by the screening platforms affiliated with the EU-OPENSCREEN initiative. It is designed as a standard source of compounds for primary screening against novel biological targets, at the request of research partners. Given the general nature of the potential applications of this compound collection, the focus of the selection strategy lies on ensuring chemical stability, absence of reactive compounds, screening-compliant physicochemical properties, loose compliance to drug-likeness criteria (as drug design is a major, but not exclusive application), and maximal diversity/coverage of chemical space, aimed at providing hits for a wide spectrum of drugable targets. Finally, practical availability/cost issues cannot be avoided. The main goal of this publication is to inform potential future users of this library about its conception, sources, and characteristics. The outline of the selection procedure, notably of the filtering rules designed by a large committee of European medicinal chemists and chemoinformaticians, may be of general methodological interest for the screening/medicinal chemistry community. The selection task of 200K molecules out of a pre-filtered set of 1.4M candidates was shared by five independent European research groups, each picking a subset of 40K compounds according to their own in-house methodology and expertise. An in-depth analysis of chemical space coverage of the library serves not only to characterize the collection, but also to compare the various chemoinformatics-driven selection procedures of maximal diversity sets. Compound selections contributed by various participating groups were mapped onto general-purpose self-organizing maps (SOMs) built on the basis of marketed drugs and bioactive reference molecules. In this way, the occupancy of chemical space by the EU-OPENSCREEN library could be directly compared with distributions of known bioactives of various classes. This mapping highlights the relevance of the selection and shows how the consensus reached by merging the five different 40K selections contributes to achieve this relevance. The approach also allows one to readily identify subsets of target- or target-class-oriented compounds from the EU-OPENSCREEN library to suit the needs of the diverse range of potential users. The final EU-OPENSCREEN library, assembled by merging five independent selections of 40K compounds from various expert groups, represents an excellent example of a Europe-wide collaborative effort toward the common objective of building best-in-class European open screening platforms.", "doi": "10.1002/cmdc.201402126", "pmid": "25044981", "labels": {"Chemical Biology Consortium Sweden": "Technology development"}, "xrefs": [], "notes": "Laboratories for Chemical Biology Ume\u00e5 (LCBU)", "created": "2017-05-04T14:56:42.045Z", "modified": "2025-10-17T13:04:29.921Z"}, {"entity": "publication", "iuid": "f2a4e13630774314a243dbe63a7d598a", "links": {"self": {"href": "https://publications.scilifelab.se/publication/f2a4e13630774314a243dbe63a7d598a.json"}, "display": {"href": "https://publications.scilifelab.se/publication/f2a4e13630774314a243dbe63a7d598a"}}, "title": "Immunomodulatory activity of commonly used drugs on Fc-receptor-mediated human natural killer cell activation.", "authors": [{"family": "Theorell", "given": "Jakob", "initials": "J"}, {"family": "Gustavsson", "given": "Anna-Lena", "initials": "AL", "orcid": "0000-0003-4332-2336", "researcher": {"href": "https://publications.scilifelab.se/researcher/6b014ef7ea0d461b8e2ddb87506b1252.json"}}, {"family": "Tesi", "given": "Bianca", "initials": "B"}, {"family": "Sigmundsson", "given": "Kristmundur", "initials": "K"}, {"family": "Ljunggren", "given": "Hans-Gustaf", "initials": "HG"}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T"}, {"family": "Bryceson", "given": "Yenan T", "initials": "YT"}], "type": "journal article", "published": "2014-06-00", "journal": {"volume": "63", "issn": "1432-0851", "issue": "6", "pages": "627-641", "title": "Cancer Immunol. Immunother.", "issn-l": "0340-7004"}, "abstract": "Natural killer (NK) cells mediate defense against neoplastic as well as infected cells. Yet, how their effector functions are affected by the large variety of pharmacological compounds commonly in use has not been investigated systematically. Here, we screened 1,200 in-use or previously approved drugs for their biological effect on freshly isolated human peripheral blood-derived NK cells. Mimicking antibody-dependent cellular cytotoxicity (ADCC), known to be important in antibody-based immunotherapies against, e.g., human malignancies, the cells were stimulated by Fc-receptor (CD16) engagement. Cellular responses were assessed by flow cytometry. Fifty-six compounds that significantly inhibited and twelve that enhanced one or more of the readouts of adhesion, exocytosis, and chemokine production were identified and confirmed as hits. Among the confirmed inhibitors, 80 % could be assigned to one of seven major pharmacological classes. These classes were \u03b22-adrenergic agonists, prostaglandins, phosphodiesterase-4 inhibitors, Ca(2+)-channel blockers, histamine H1-receptor antagonists, serotonin/dopamine receptor antagonists, and topoisomerase inhibitors that displayed distinct inhibitory patterns on NK cell responses. Among observed enhancers, interestingly, two ergosterol synthesis inhibitors were identified that specifically promoted exocytosis. In summary, these results provide a comprehensive knowledge base of the effect known drugs have on NK cells. More specifically, they provide an overview of drugs that may modulate NK cell-mediated ADCC in the context of clinical immunotherapies.", "doi": "10.1007/s00262-014-1539-6", "pmid": "24682538", "labels": {"Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [], "notes": [], "created": "2017-10-20T15:09:03.126Z", "modified": "2025-10-17T13:04:30.023Z"}, {"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"}, {"entity": "publication", "iuid": "b695a1f42a0f4417b066ba2e33a3d879", "links": {"self": {"href": "https://publications.scilifelab.se/publication/b695a1f42a0f4417b066ba2e33a3d879.json"}, "display": {"href": "https://publications.scilifelab.se/publication/b695a1f42a0f4417b066ba2e33a3d879"}}, "title": "Structure-activity relationships of synthetic cordycepin analogues as experimental therapeutics for African trypanosomiasis.", "authors": [{"family": "Vodnala", "given": "Suman K", "initials": "SK"}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T"}, {"family": "Yeheskieli", "given": "Esther", "initials": "E"}, {"family": "Sj\u00f6berg", "given": "Birger", "initials": "B"}, {"family": "Gustavsson", "given": "Anna-Lena", "initials": "AL", "orcid": "0000-0003-4332-2336", "researcher": {"href": "https://publications.scilifelab.se/researcher/6b014ef7ea0d461b8e2ddb87506b1252.json"}}, {"family": "Svensson", "given": "Richard", "initials": "R"}, {"family": "Olivera", "given": "Gabriela C", "initials": "GC"}, {"family": "Eze", "given": "Anthonius A", "initials": "AA"}, {"family": "de Koning", "given": "Harry P", "initials": "HP"}, {"family": "Hammarstr\u00f6m", "given": "Lars G J", "initials": "LG"}, {"family": "Rottenberg", "given": "Martin E", "initials": "ME"}], "type": "journal article", "published": "2013-12-27", "journal": {"volume": "56", "issn": "1520-4804", "issue": "24", "pages": "9861-9873", "title": "J. Med. Chem.", "issn-l": "0022-2623"}, "abstract": "Novel methods for treatment of African trypanosomiasis, caused by infection with Trypanosoma brucei are needed. Cordycepin (3'-deoxyadenosine, 1a) is a powerful trypanocidal compound in vitro but is ineffective in vivo because of rapid metabolic degradation by adenosine deaminase (ADA). We elucidated the structural moieties of cordycepin required for trypanocidal activity and designed analogues that retained trypanotoxicity while gaining resistance to ADA-mediated metabolism. 2-Fluorocordycepin (2-fluoro-3'-deoxyadenosine, 1b) was identified as a selective, potent, and ADA-resistant trypanocidal compound that cured T. brucei infection in mice. Compound 1b is transported through the high affinity TbAT1/P2 adenosine transporter and is a substrate of T. b. brucei adenosine kinase. 1b has good preclinical properties suitable for an oral drug, albeit a relatively short plasma half-life. We present a rapid and efficient synthesis of 2-halogenated cordycepins, also useful synthons for the development of additional novel C2-substituted 3'-deoxyadenosine analogues to be evaluated in development of experimental therapeutics.", "doi": "10.1021/jm401530a", "pmid": "24283924", "labels": {"Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [], "notes": "Uppsala Drug Optimization and Pharmaceutical Profiling (UDOPP)\r\nADME of Therapeutics (UDOPP)", "created": "2017-05-04T14:56:48.005Z", "modified": "2025-10-17T13:04:30.196Z"}, {"entity": "publication", "iuid": "f860b4e98f3044179bb6ac075c1296ff", "links": {"self": {"href": "https://publications.scilifelab.se/publication/f860b4e98f3044179bb6ac075c1296ff.json"}, "display": {"href": "https://publications.scilifelab.se/publication/f860b4e98f3044179bb6ac075c1296ff"}}, "title": "Ebsulfur is a benzisothiazolone cytocidal inhibitor targeting the trypanothione reductase of Trypanosoma brucei.", "authors": [{"family": "Lu", "given": "Jun", "initials": "J"}, {"family": "Vodnala", "given": "Suman K", "initials": "SK"}, {"family": "Gustavsson", "given": "Anna-Lena", "initials": "AL", "orcid": "0000-0003-4332-2336", "researcher": {"href": "https://publications.scilifelab.se/researcher/6b014ef7ea0d461b8e2ddb87506b1252.json"}}, {"family": "Gustafsson", "given": "Tomas N", "initials": "TN"}, {"family": "Sj\u00f6berg", "given": "Birger", "initials": "B"}, {"family": "Johansson", "given": "Henrik A", "initials": "HA"}, {"family": "Kumar", "given": "Sangit", "initials": "S"}, {"family": "Tjernberg", "given": "Agneta", "initials": "A"}, {"family": "Engman", "given": "Lars", "initials": "L"}, {"family": "Rottenberg", "given": "Martin E", "initials": "ME"}, {"family": "Holmgren", "given": "Arne", "initials": "A"}], "type": "journal article", "published": "2013-09-20", "journal": {"volume": "288", "issn": "1083-351X", "issue": "38", "pages": "27456-27468", "title": "J. Biol. Chem.", "issn-l": "0021-9258"}, "abstract": "Trypanosoma brucei is the causing agent of African trypanosomiasis. These parasites possess a unique thiol redox system required for DNA synthesis and defense against oxidative stress. It includes trypanothione and trypanothione reductase (TryR) instead of the thioredoxin and glutaredoxin systems of mammalian hosts. Here, we show that the benzisothiazolone compound ebsulfur (EbS), a sulfur analogue of ebselen, is a potent inhibitor of T. brucei growth with a favorable selectivity index over mammalian cells. EbS inhibited the TryR activity and decreased non-protein thiol levels in cultured parasites. The inhibition of TryR by EbS was irreversible and NADPH-dependent. EbS formed a complex with TryR and caused oxidation and inactivation of the enzyme. EbS was more toxic for T. brucei than for Trypanosoma cruzi, probably due to lower levels of TryR and trypanothione in T. brucei. Furthermore, inhibition of TryR produced high intracellular reactive oxygen species. Hydrogen peroxide, known to be constitutively high in T. brucei, enhanced the EbS inhibition of TryR. The elevation of reactive oxygen species production in parasites caused by EbS induced a programmed cell death. Soluble EbS analogues were synthesized and cured T. brucei brucei infection in mice when used together with nifurtimox. Altogether, EbS and EbS analogues disrupt the trypanothione system, hampering the defense against oxidative stress. Thus, EbS is a promising lead for development of drugs against African trypanosomiasis.", "doi": "10.1074/jbc.M113.495101", "pmid": "23900839", "labels": {"Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [{"db": "pii", "key": "S0021-9258(20)49012-X"}, {"db": "pmc", "key": "PMC3779740"}], "notes": [], "created": "2017-10-20T14:49:29.162Z", "modified": "2025-10-17T13:04:30.291Z"}, {"entity": "publication", "iuid": "38c3875a34454e4da87d1656e59b66ce", "links": {"self": {"href": "https://publications.scilifelab.se/publication/38c3875a34454e4da87d1656e59b66ce.json"}, "display": {"href": "https://publications.scilifelab.se/publication/38c3875a34454e4da87d1656e59b66ce"}}, "title": "Design of a highly selective and potent class of non-planar estrogen receptor \u03b2 agonists.", "authors": [{"family": "Sund\u00e9n", "given": "Henrik", "initials": "H"}, {"family": "Ma", "given": "Jian-Nong", "initials": "JN"}, {"family": "Hansen", "given": "Lars K", "initials": "LK"}, {"family": "Gustavsson", "given": "Anna-Lena", "initials": "AL", "orcid": "0000-0003-4332-2336", "researcher": {"href": "https://publications.scilifelab.se/researcher/6b014ef7ea0d461b8e2ddb87506b1252.json"}}, {"family": "Burstein", "given": "Ethan S", "initials": "ES"}, {"family": "Olsson", "given": "Roger", "initials": "R"}], "type": "journal article", "published": "2013-08-00", "journal": {"volume": "8", "issn": "1860-7187", "issue": "8", "pages": "1283-1294", "title": "ChemMedChem", "issn-l": "1860-7179"}, "abstract": "Selective activation of the estrogen receptor \u03b2 (ER\u03b2) could be a safe approach to hormone replacement therapy for both women and men, in contrast to the estrogens currently used for women which activate both ER\u03b2 and ER\u03b1, occasionally causing severe side effects. The selective ER\u03b2 agonist AC-131 has shown efficacy in animal models of Parkinson's disease and neuropathic pain. With the use of AC-131 as template, herein we report the discovery, synthesis, and structure-activity relationship (SAR) study of a new class of dihydrobenzofurans as potent and selective ER\u03b2 agonists. The SAR was established by enantioselective synthesis, molecular modeling, and whole-cell-based functional assays. The most potent diastereomer, cis-10-SR, was shown to have an EC50 value of <1 nM, potency 100-fold higher than that of AC-131. Even more interestingly, compound trans-10-SS exhibited 1000-fold ER\u03b2/ER\u03b1 selectivity while still maintaining good potency (\u223c10 nM). In addition, trans-10-SS showed only partial agonist activity (30-60 % Eff.) toward ER\u03b1 at 10 \u03bcM. This unprecedented selectivity could be rationalized by molecular modeling. Compound trans-10-SS appears to be the first molecule to take advantage of both conservative amino acid differences found in the \u03b1- and \u03b2-faces of the binding cavities of ER\u03b1 and ER\u03b2.", "doi": "10.1002/cmdc.201300175", "pmid": "23784708", "labels": {"Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [], "notes": [], "created": "2017-10-20T14:59:35.171Z", "modified": "2025-10-17T13:04:30.324Z"}, {"entity": "publication", "iuid": "c282a323456c429f85c223e3604521ac", "links": {"self": {"href": "https://publications.scilifelab.se/publication/c282a323456c429f85c223e3604521ac.json"}, "display": {"href": "https://publications.scilifelab.se/publication/c282a323456c429f85c223e3604521ac"}}, "title": "The A-CD analogue of 16\u03b2,17\u03b1-estriol is a potent and highly selective estrogen receptor \u03b2 agonist", "authors": [{"family": "Sauv\u00e9e", "given": "Claire", "initials": "C"}, {"family": "Sch\u00e4fer", "given": "Anja", "initials": "A"}, {"family": "Sund\u00e9n", "given": "Henrik", "initials": "H"}, {"family": "Ma", "given": "Jian Nong", "initials": "JN"}, {"family": "Gustavsson", "given": "Anna Lena", "initials": "AL", "orcid": "0000-0003-4332-2336", "researcher": {"href": "https://publications.scilifelab.se/researcher/6b014ef7ea0d461b8e2ddb87506b1252.json"}}, {"family": "Burstein", "given": "Ethan S", "initials": "ES"}, {"family": "Olsson", "given": "Roger", "initials": "R"}], "type": "journal-article", "published": "2013-00-00", "journal": {"volume": "4", "issn": "2040-2503", "issue": "11", "pages": "1439", "title": "Med. Chem. Commun.", "issn-l": null}, "abstract": null, "doi": "10.1039/c3md00194f", "pmid": null, "labels": {"Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [], "notes": [], "created": "2017-10-20T14:58:21.405Z", "modified": "2025-10-17T13:04:30.475Z"}]}