Discovery of the First-in-class G9a/GLP PROTAC Degrader

Abstract

AbstractAberrantly 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.10induces 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,10displays superior cell growth inhibition to the parent G9a/GLP inhibitor UNC0642 in prostate, leukemia, and lung cancer cells and has suitable mouse pharmacokinetic properties forin vivoefficacy studies. Overall,10is a valuable chemical biology tool to further investigate the functions of G9a/GLP and a potential therapeutic for treating G9a/GLP-dependent cancers.Graphical Abstract