Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
Nat Chem Biol. 2011 Jul 10;7(8):566-74. doi: 10.1038/nchembio.599.
Protein lysine methyltransferases G9a and GLP modulate the transcriptional repression of a variety of genes via dimethylation of Lys9 on histone H3 (H3K9me2) as well as dimethylation of non-histone targets. Here we report the discovery of UNC0638, an inhibitor of G9a and GLP with excellent potency and selectivity over a wide range of epigenetic and non-epigenetic targets. UNC0638 treatment of a variety of cell lines resulted in lower global H3K9me2 levels, equivalent to levels observed for small hairpin RNA knockdown of G9a and GLP with the functional potency of UNC0638 being well separated from its toxicity. UNC0638 markedly reduced the clonogenicity of MCF7 cells, reduced the abundance of H3K9me2 marks at promoters of known G9a-regulated endogenous genes and disproportionately affected several genomic loci encoding microRNAs. In mouse embryonic stem cells, UNC0638 reactivated G9a-silenced genes and a retroviral reporter gene in a concentration-dependent manner without promoting differentiation.
蛋白赖氨酸甲基转移酶 G9a 和 GLP 通过组蛋白 H3 赖氨酸 9 位的二甲基化（H3K9me2）以及非组蛋白靶标的二甲基化来调节多种基因的转录抑制。在这里，我们报告了 UNC0638 的发现，UNC0638 是 G9a 和 GLP 的抑制剂，对广泛的表观遗传和非表观遗传靶标具有优异的效力和选择性。UNC0638 处理多种细胞系导致全局 H3K9me2 水平降低，与小发夹 RNA 敲低 G9a 和 GLP 观察到的水平相当，UNC0638 的功能效力与其毒性明显分离。UNC0638 显著降低 MCF7 细胞的集落形成能力，降低已知 G9a 调节的内源性基因启动子处 H3K9me2 标记的丰度，并不成比例地影响多个编码 microRNAs 的基因组位点。在小鼠胚胎干细胞中，UNC0638 以浓度依赖的方式重新激活 G9a 沉默的基因和逆转录病毒报告基因，而不促进分化。
