{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:11:48Z","timestamp":1791267108872,"version":"4.1.0"},"reference-count":21,"publisher":"Wiley","issue":"33","license":[{"start":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T00:00:00Z","timestamp":1747267200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010767","name":"Innovative Medicines Initiative","doi-asserted-by":"publisher","award":["875510"],"award-info":[{"award-number":["875510"]}],"id":[{"id":"10.13039\/501100010767","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007435","name":"\u00c5ke Wiberg Stiftelse","doi-asserted-by":"publisher","award":["M23\u20100043"],"award-info":[{"award-number":["M23\u20100043"]}],"id":[{"id":"10.13039\/100007435","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006313","name":"Barncancerfonden","doi-asserted-by":"publisher","award":["PR2021\u20100030"],"award-info":[{"award-number":["PR2021\u20100030"]}],"id":[{"id":"10.13039\/501100006313","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2022\u201003681"],"award-info":[{"award-number":["2022\u201003681"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF23OC0084420"],"award-info":[{"award-number":["NNF23OC0084420"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002794","name":"Cancerfonden","doi-asserted-by":"publisher","award":["CAN2021\/1490"],"award-info":[{"award-number":["CAN2021\/1490"]}],"id":[{"id":"10.13039\/501100002794","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chemistry A European J"],"published-print":{"date-parts":[[2025,6,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    8\u2010oxoGuanine DNA glycosylase 1 (OGG1) is the first known target of organocatalytic switches (ORCAs), which rewrite the biochemical function of the enzyme through redirection of its preferred substrate from 8\u2010oxoG to AP sites. Previously, different ORCA chemotypes were shown to enhance the operational pH window for OGG1, possibly through direct involvement in proton transfer events during DNA strand cleavage. Accordingly, compound pK\n                    <jats:sub>a<\/jats:sub>\n                    is a crucial and necessary consideration for the identification and application of future OGG1 ORCAs. Here, we identify a minimal structure of organocatalytic switches\u20134\u2010anilino pyridines and 6\u2010anilino pyrimidines\u2013which are dimethyl\u2010amino\u2010pyridine (DMAP)\u2010type Br\u00f8nsted bases binding the active site of OGG1. Systematic interrogation of compound basicity through modulation of electron\u2010withdrawing (EWG) and electron\u2010donating (EDG) substituents reveals that a pK\n                    <jats:sub>a<\/jats:sub>\n                    less or equal to the assay pH is a viable parameter for prediction of compound activity. The lead structure (AC\n                    <jats:sub>50<\/jats:sub>\n                    13\u00a0nM, pK\n                    <jats:sub>a<\/jats:sub>\n                    7.0) was then identified as a potent scaffold from a screen in a patient\u2010derived 3D model of metabolic dysfunction\u2010associated steatohepatitis (MASH), where it reduced hepatic fibrosis by 35%. Collectively, these findings deepen the knowledge of this novel modulator class, with important implications for future enzyme targets and probe development.\n                  <\/jats:p>","DOI":"10.1002\/chem.202500382","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T15:48:42Z","timestamp":1745855322000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Organocatalytic Switches of DNA Glycosylase OGG1 Catalyze a Highly Efficient AP\u2010Lyase Function"],"prefix":"10.1002","volume":"31","author":[{"given":"Mario","family":"Kehler","sequence":"first","affiliation":[{"name":"Science for Life Laboratory Department of Oncology\u2010Pathology Karolinska\u00a0Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaixin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory Department of Oncology\u2010Pathology Karolinska\u00a0Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurino M.","family":"Kemas","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology Karolinska Institutet  Stockholm Sweden"},{"name":"Center for Molecular Medicine Karolinska\u00a0Institutet and Karolinska Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"del Prado","sequence":"additional","affiliation":[{"name":"Centro\u00a0de\u00a0Biolog\u00eda\u00a0Molecular 'Severo Ochoa' (CSIC\u2010UAM)  Nicol\u00e1s Cabrera 1 Cantoblanco Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma Scaletti","family":"Hutchinson","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics Stockholm University  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elinor Hesslefors","family":"Nairn","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory Department of Oncology\u2010Pathology Karolinska\u00a0Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marek","family":"Varga","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory Department of Oncology\u2010Pathology Karolinska\u00a0Institutet  Stockholm Sweden"},{"name":"EaStCHEM School of Chemistry University of St. Andrews  St. Andrews UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne","family":"Plattner","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology Karolinska Institutet  Stockholm Sweden"},{"name":"Center for Molecular Medicine Karolinska\u00a0Institutet and Karolinska Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology Karolinska Institutet  Stockholm Sweden"},{"name":"Center for Molecular Medicine Karolinska\u00a0Institutet and Karolinska Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oryn","family":"Purewal\u2010Sidhu","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory Department of Oncology\u2010Pathology Karolinska\u00a0Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Haslam","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory Department of Oncology\u2010Pathology Karolinska\u00a0Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elis\u00e9e","family":"Wiita","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory Department of Oncology\u2010Pathology Karolinska\u00a0Institutet  Stockholm 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Karolinska\u00a0Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Femke M.","family":"Hormann","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory Department of Oncology\u2010Pathology Karolinska\u00a0Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang\u2010Cheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine Karolinska\u00a0Institutet and Karolinska Hospital  Stockholm Sweden"},{"name":"Structural Genomics Consortium Department of Medicine Solna Karolinska\u00a0Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olov","family":"Wallner","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory Department of Oncology\u2010Pathology Karolinska\u00a0Institutet  Stockholm 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G.","family":"Rudd","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory Department of Oncology\u2010Pathology Karolinska\u00a0Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e5l","family":"Stenmark","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics Stockholm University  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"de Vega","sequence":"additional","affiliation":[{"name":"Centro\u00a0de\u00a0Biolog\u00eda\u00a0Molecular 'Severo Ochoa' (CSIC\u2010UAM)  Nicol\u00e1s Cabrera 1 Cantoblanco Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Helleday","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory Department of Oncology\u2010Pathology Karolinska\u00a0Institutet  Stockholm Sweden"},{"name":"Sheffield Cancer Centre Department of Oncology and Metabolism 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