G9a and G9a-like protein (GLP) are euchromatic histone-lysine methyltransferases (EHMT2 and EHMT1, respectively) that can heterodimerize with each other to methylate several proteins in addition to histone H3. UNC0646 is a potent and selective inhibitor of G9a and GLP activities in vitro (IC50s = 6 and 15 nM, respectively) and G9a/GLP-mediated dimethylation of histone 3 on lysine 9 in MDA-MB-231 cells (IC50 = 26 nM). It is highly selective for G9a/GLP over several other protein lysine and arginine methyltransferases. UNC0646 potently inhibits G9a/GLP activity in a variety of cancer cell lines as well as in the human fetal lung IMR-90 line. This compound selectively targets the corepressor function of G9a without affecting its ability to act as a coactivator with glucocorticoid receptor.
