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

Aberrantly expressed lysine methyltransferases G9a and
GLP, which
catalyze mono- and dimethylation of histone H3 lysine 9 (H3K9), have
been implicated in numerous cancers. Recent studies have uncovered
both catalytic and noncatalytic 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. Futhermore, 10 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.