{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"submitter":["Velez J"],"funding":["NCI NIH HHS","NIH HHS"],"pubmed_abstract":["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, <b>10</b> (MS8709), as a potential anticancer therapeutic. <b>10</b> 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, <b>10</b> 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 <i>in vivo</i> efficacy studies. Overall, <b>10</b> is a valuable chemical biology tool to further investigate the functions of G9a/GLP and a potential therapeutic for treating G9a/GLP-dependent cancers."],"journal":["bioRxiv : the preprint server for biology"],"pagination":["2024.02.26.582210"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10925177"],"repository":["biostudies-literature"],"pubmed_title":["Discovery of the First-in-class G9a/GLP PROTAC Degrader."],"pmcid":["PMC10925177"],"funding_grant_id":["P30 CA196521","S10 OD025132","T32 CA078207","S10 OD028504"],"pubmed_authors":["Xiong Y","Yim H","Kaniskan HU","Yang P","Deng Z","Han Y","Kabir M","Jin J","Park KS","Velez J"],"additional_accession":[]},"is_claimable":false,"name":"Discovery of the First-in-class G9a/GLP PROTAC Degrader.","description":"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, <b>10</b> (MS8709), as a potential anticancer therapeutic. <b>10</b> 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, <b>10</b> 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 <i>in vivo</i> efficacy studies. Overall, <b>10</b> is a valuable chemical biology tool to further investigate the functions of G9a/GLP and a potential therapeutic for treating G9a/GLP-dependent cancers.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Feb","modification":"2026-04-08T18:30:49.548Z","creation":"2025-02-19T04:41:53.319Z"},"accession":"S-EPMC10925177","cross_references":{"pubmed":["38464025"],"doi":["10.1101/2024.02.26.582210"]}}