biostudies-literatureUnknownVelez JNCI NIH HHSNIH HHSAberrantly 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, 10 (MS8709), as a potential anticancer therapeutic. 10 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, 10 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 in vivo efficacy studies. Overall, 10 is a valuable chemical biology tool to further investigate the functions of G9a/GLP and a potential therapeutic for treating G9a/GLP-dependent cancers.bioRxiv : the preprint server for biology2024.02.26.582210https://www.ebi.ac.uk/biostudies/studies/S-EPMC10925177biostudies-literatureDiscovery of the First-in-class G9a/GLP PROTAC Degrader.PMC10925177P30 CA196521S10 OD025132T32 CA078207S10 OD028504Xiong YYim HKaniskan HUYang PDeng ZHan YKabir MJin JPark KSVelez JfalseDiscovery of the First-in-class G9a/GLP PROTAC Degrader.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, 10 (MS8709), as a potential anticancer therapeutic. 10 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, 10 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 in vivo efficacy studies. Overall, 10 is a valuable chemical biology tool to further investigate the functions of G9a/GLP and a potential therapeutic for treating G9a/GLP-dependent cancers.2024-01-01T00:00:00Z2024 Feb2026-04-08T18:30:49.548Z2025-02-19T04:41:53.319ZS-EPMC109251773846402510.1101/2024.02.26.582210