{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:00:57Z","timestamp":1768510857915,"version":"3.49.0"},"posted":{"date-parts":[[2024,2,29]]},"group-title":"Biochemistry","reference-count":57,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,2,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Aberrantly expressed lysine methyltransferases G9a and GLP, which catalyze mono- and di-methylation of histone H3 lysine 9 (H3K9), have been implicated in numerous cancers. Recent studies have uncovered both catalytic and non-catalytic oncogenic functions of G9a\/GLP. As such, G9a\/GLP catalytic inhibitors have displayed limited anticancer activity. Here, we report the discovery of the first-in-class G9a\/GLP proteolysis targeting chimera (PROTAC) degrader,\n                  <jats:bold>10<\/jats:bold>\n                  (MS8709), as a potential anticancer therapeutic.\n                  <jats:bold>10<\/jats:bold>\n                  induces G9a\/GLP degradation in a concentration-, time, and ubiquitin-proteasome system (UPS)-dependent manner, does not alter the mRNA expression of G9a\/GLP and is selective for G9a\/GLP over other methyltransferases. Moreover,\n                  <jats:bold>10<\/jats:bold>\n                  displays superior cell growth inhibition to the parent G9a\/GLP inhibitor UNC0642 in prostate, leukemia, and lung cancer cells and has suitable mouse pharmacokinetic properties for\n                  <jats:italic>in vivo<\/jats:italic>\n                  efficacy studies. Overall,\n                  <jats:bold>10<\/jats:bold>\n                  is a valuable chemical biology tool to further investigate the functions of G9a\/GLP and a potential therapeutic for treating G9a\/GLP-dependent cancers.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"582210v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2024.02.26.582210","type":"posted-content","created":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T08:45:20Z","timestamp":1709196320000},"source":"Crossref","is-referenced-by-count":2,"title":["Discovery of the First-in-class G9a\/GLP PROTAC Degrader"],"prefix":"10.64898","author":[{"given":"Julia","family":"Velez","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yulin","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyerin","family":"Yim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peiyi","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhijie","family":"Deng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kwang-su","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Md","family":"Kabir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H. \u00dcmit","family":"Kaniskan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Jin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024030404250609000_2024.02.26.582210v1.1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1284005"},{"key":"2024030404250609000_2024.02.26.582210v1.2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.2027411"},{"key":"2024030404250609000_2024.02.26.582210v1.3","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M101914200"},{"key":"2024030404250609000_2024.02.26.582210v1.4","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-08-0497"},{"key":"2024030404250609000_2024.02.26.582210v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1560"},{"key":"2024030404250609000_2024.02.26.582210v1.6","doi-asserted-by":"publisher","DOI":"10.1101\/gad.989402"},{"key":"2024030404250609000_2024.02.26.582210v1.7","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-0101"},{"issue":"11","key":"2024030404250609000_2024.02.26.582210v1.8","doi-asserted-by":"crossref","first-page":"e0188051","DOI":"10.1371\/journal.pone.0188051","article-title":"Inhibition of the H3K9 methyltransferase G9a attenuates oncogenicity and activates the hypoxia signaling pathway","volume":"12","year":"2017","journal-title":"PLoS One"},{"key":"2024030404250609000_2024.02.26.582210v1.9","doi-asserted-by":"crossref","unstructured":"Jan, S. ; Dar, M. 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