{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T21:29:45Z","timestamp":1792099785857,"version":"4.4.0"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T00:00:00Z","timestamp":1618358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004329","name":"Javna Agencija za Raziskovalno Dejavnost RS","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Chem."],"abstract":"<jats:p>O-GlcNAcylation is an important post-translational and metabolic process in cells that must be carefully regulated. O-GlcNAc transferase (OGT) is ubiquitously present in cells and is the only enzyme that catalyzes the transfer of O-GlcNAc to proteins. OGT is a promising target in various pathologies such as cancer, immune system diseases, or nervous impairment. In our previous work we identified the 2-oxo-1,2-dihydroquinoline-4-carboxamide derivatives as promising compounds by a fragment-based drug design approach. Herein, we report the extension of this first series with several new fragments. As the most potent fragment, we identified <jats:bold>3b<\/jats:bold> with an IC<jats:sub>50<\/jats:sub> value of 116.0 \u03bcM. If compared with the most potent inhibitor of the first series, <jats:bold>F20<\/jats:bold> (IC<jats:sub>50<\/jats:sub> = 117.6 \u03bcM), we can conclude that the new fragments did not improve OGT inhibition remarkably. Therefore, <jats:bold>F20<\/jats:bold> was used as the basis for the design of a series of compounds with the elongation toward the O-GlcNAc binding pocket as the free carboxylate allows easy conjugation. Compound <jats:bold>6b<\/jats:bold> with an IC<jats:sub>50<\/jats:sub> value of 144.5 \u03bcM showed the most potent OGT inhibition among the elongated compounds, but it loses inhibition potency when compared to the UDP mimetic <jats:bold>F20<\/jats:bold>. We therefore assume that the binding of the compounds in the O-GlcNAc binding pocket is likely not crucial for OGT inhibition. Furthermore, evaluation of the compounds with two different assays revealed that some inhibitors most likely interfere with the commercially available UDP-Glo\u2122 glycosyltransferase assay, leading to false positive results. This observation calls for caution, when evaluating UDP mimetic as OGT inhibitors with the UDP-Glo\u2122 glycosyltransferase assay, as misinterpretations can occur.<\/jats:p>","DOI":"10.3389\/fchem.2021.666122","type":"journal-article","created":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T08:06:42Z","timestamp":1618387602000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["New Quinolinone O-GlcNAc Transferase Inhibitors Based on Fragment Growth"],"prefix":"10.3389","volume":"9","author":[{"given":"Matja\u017e","family":"Weiss","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena M.","family":"Loi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u0161a","family":"Sterle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyril","family":"Balsollier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tihomir","family":"Toma\u0161i\u010d","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland J.","family":"Pieters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Gobec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marko","family":"Anderluh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3943","DOI":"10.1002\/1873-3468.13159","article-title":"T cell development and the physiological role of O-GlcNAc","volume":"592","author":"Abramowitz","year":"2018","journal-title":"FEBS Lett."},{"key":"B2","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1042\/BJ20131272","article-title":"Bisubstrate UDP-peptide conjugates as human O-GlcNAc transferase inhibitors","volume":"457","author":"Borodkin","year":"2014","journal-title":"Biochem. J."},{"key":"B3","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.bbagen.2009.07.018","article-title":"O-linked \u03b2-N-acetylglucosamine (O-GlcNAc): extensive crosstalk with phosphorylation to regulate signaling and transcription in response to nutrients and stress","volume":"1800","author":"Butkinaree","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"B4","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/j.bbrc.2012.04.124","article-title":"O-GlcNAcylation of Kinases","volume":"422","author":"Dias","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B5","doi-asserted-by":"publisher","first-page":"3282","DOI":"10.1016\/j.jmb.2016.05.028","article-title":"O-GlcNAcylation in cancer biology: linking metabolism and signaling","volume":"428","author":"Ferrer","year":"2016","journal-title":"J. Mol. Biol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"9005","DOI":"10.1016\/S0021-9258(19)50380-5","article-title":"Glycosylation of nuclear and cytoplasmic proteins. Purification and characterization of a uridine diphospho-N-acetylglucosamine: polypeptide \u03b2-N-Acetylglucosaminyltransferase","volume":"267","author":"Haltiwanger","year":"1992","journal-title":"J. Biol. Chem"},{"key":"B7","doi-asserted-by":"publisher","first-page":"2563","DOI":"10.1016\/S0021-9258(19)39838-2","article-title":"Enzymatic addition of O-GlcNAc to nuclear and Cytoplasmic proteins: identification of a uridine diphospho-N-acetylglucosamine: peptide \u00df-N-acetylglucosaminyltransferase","volume":"265","author":"Haltiwanger","year":"1990","journal-title":"J. Biol. Chem."},{"key":"B8","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1146\/annurev-biochem-060608-102511","article-title":"Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease","volume":"80","author":"Hart","year":"2011","journal-title":"Annu. Rev. Biochem."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1771","DOI":"10.1021\/acs.jcim.5b00142","article-title":"POSIT: flexible shape-guided docking for pose prediction","volume":"55","author":"Kelley","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"B10","doi-asserted-by":"publisher","first-page":"9308","DOI":"10.1074\/jbc.272.14.9308","article-title":"Dynamic glycosylation of nuclear and cytosolic proteins: cloning and characterization of a unique O-GlcNAc transferase with multiple tetratricopeptide repeats","volume":"272","author":"Kreppel","year":"1997","journal-title":"J. Biol. Chem."},{"key":"B11","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1038\/nchembio.1109","article-title":"Structural snapshots of the reaction coordinate for O-GlcNAc transferase","volume":"8","author":"Lazarus","year":"2012","journal-title":"Nat. Chem. Biol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"415","DOI":"10.3389\/fendo.2018.00415","article-title":"O-GlcNAc: a sweetheart of the cell cycle and DNA damage response","volume":"9","author":"Liu","year":"2018","journal-title":"Front. Endocrinol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/1559-0275-11-8","article-title":"O-GlcNAc profiling: from proteins to proteomes","volume":"11","author":"Ma","year":"2014","journal-title":"Clin. Proteomics"},{"key":"B14","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1007\/s00726-013-1543-8","article-title":"O-GlcNAc in cancer biology","volume":"45","author":"Ma","year":"2013","journal-title":"Amino Acids"},{"key":"B15","doi-asserted-by":"publisher","first-page":"34449","DOI":"10.1074\/jbc.R114.585984","article-title":"Protein O-GlcNAcylation and cardiovascular (patho) physiology","volume":"289","author":"Marsh","year":"2014","journal-title":"J. Biol. Chem."},{"key":"B16","doi-asserted-by":"publisher","first-page":"13542","DOI":"10.1021\/jacs.8b07328","article-title":"Structure-based evolution of low nanomolar O-GlcNAc transferase inhibitors","volume":"140","author":"Martin","year":"2018","journal-title":"J. Am. Chem. Soc."},{"key":"B17","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1021\/ci100436p","article-title":"FRED pose prediction and virtual screening accuracy","volume":"51","author":"McGann","year":"2011","journal-title":"J. Chem. Inf. Model."},{"key":"B18","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1007\/s10822-012-9584-8","article-title":"FRED and HYBRID docking performance on standardized datasets","volume":"26","author":"McGann","year":"2012","journal-title":"J. Comput. Aided. Mol. Des."},{"key":"B19","unstructured":"2020"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1392","DOI":"10.1021\/acschembio.5b00004","article-title":"A small molecule that inhibits OGT activity in cells","volume":"10","author":"Ortiz-Meoz","year":"2015","journal-title":"ACS Chem. Biol."},{"key":"B21","unstructured":"UDP-GloTM Glycosyltransferase Assay2020"},{"key":"B22","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.bbrc.2011.03.115","article-title":"Denitrosylation of S-nitrosylated OGT is iriggered in LPS-Stimulated innate immune response","volume":"408","author":"Ryu","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B23","doi-asserted-by":"publisher","first-page":"19915","DOI":"10.1073\/pnas.1009023107","article-title":"\u03b2-N-Acetylglucosamine (O-GlcNAc) is part of the histone code","volume":"107","author":"Sakabe","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B24","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/S0021-9258(17)43295-9","article-title":"Topography and polypeptide distribution of terminal N-acetylglucosamine residues on the surfaces of intact lymphocytes","volume":"259","author":"Torres","year":"1984","journal-title":"J. Biol. Chem."},{"key":"B25","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1042\/BST20150189","article-title":"O-GlcNAc transferase inhibitors: current tools and future challenges","volume":"44","author":"Trapannone","year":"2016","journal-title":"Biochem. Soc. Trans."},{"key":"B26","doi-asserted-by":"publisher","first-page":"9601","DOI":"10.1002\/anie.202000621","article-title":"A direct fluorescent activity assay for glycosyltransferases enables convenient high-throughput screening: application to O-GlcNAc transferase","volume":"59","author":"Vocadlo","year":"2020","journal-title":"Angew. Chemie Int. Ed."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.1038\/ncb1470","article-title":"Modification of P53 with O-linked N-acetylglucosamine regulates P53 activity and stability","volume":"8","author":"Yang","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"6839","DOI":"10.1039\/C4CS00038B","article-title":"O-GlcNAc and neurodegeneration: biochemical mechanisms and potential roles in Alzheimer's disease and beyond","volume":"43","author":"Yuzwa","year":"2014","journal-title":"Chem. Soc. Rev."},{"key":"B29","volume-title":"Method for Quantifying 5-Hydroxymethylcytosine","author":"Zegzouti","year":"2014"},{"key":"B30","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1039\/C8MD00115D","article-title":"Inhibition of O -GlcNAc transferase (OGT) by peptidic hybrids","volume":"9","author":"Zhang","year":"2018","journal-title":"Medchemcomm"}],"container-title":["Frontiers in Chemistry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2021.666122\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T08:07:03Z","timestamp":1618387623000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2021.666122\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,14]]},"references-count":30,"alternative-id":["10.3389\/fchem.2021.666122"],"URL":"https:\/\/doi.org\/10.3389\/fchem.2021.666122","relation":{},"ISSN":["2296-2646"],"issn-type":[{"value":"2296-2646","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,14]]},"article-number":"666122"}}