Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase

G9a-like
protein (GLP) and G9a are highly homologous protein lysine
methyltransferases (PKMTs) sharing approximately 80% sequence identity
in their catalytic domains. GLP and G9a form a heterodimer complex
and catalyze mono- and dimethylation of histone H3 lysine 9 and nonhistone
substrates. Although they are closely related, GLP and G9a possess
distinct physiological and pathophysiological functions. Thus, GLP
or G9a selective small-molecule inhibitors are useful tools to dissect
their distinct biological functions. We previously reported potent
and selective G9a/GLP dual inhibitors including UNC0638 and UNC0642.
Here we report the discovery of potent and selective GLP inhibitors
including 4 (MS0124) and 18 (MS012), which
are >30-fold and 140-fold selective for GLP over G9a and other
methyltransferases,
respectively. The cocrystal structures of GLP and G9a in the complex
with either 4 or 18 displayed virtually
identical binding modes and interactions, highlighting the challenges
in structure-based design of selective inhibitors for either enzyme.