Epizyme, Inc., Cambridge, MA, USA.
Nat Chem Biol. 2012 Nov;8(11):890-6. doi: 10.1038/nchembio.1084. Epub 2012 Sep 30.
EZH2 catalyzes trimethylation of histone H3 lysine 27 (H3K27). Point mutations of EZH2 at Tyr641 and Ala677 occur in subpopulations of non-Hodgkin's lymphoma, where they drive H3K27 hypertrimethylation. Here we report the discovery of EPZ005687, a potent inhibitor of EZH2 (K(i) of 24 nM). EPZ005687 has greater than 500-fold selectivity against 15 other protein methyltransferases and has 50-fold selectivity against the closely related enzyme EZH1. The compound reduces H3K27 methylation in various lymphoma cells; this translates into apoptotic cell killing in heterozygous Tyr641 or Ala677 mutant cells, with minimal effects on the proliferation of wild-type cells. These data suggest that genetic alteration of EZH2 (for example, mutations at Tyr641 or Ala677) results in a critical dependency on enzymatic activity for proliferation (that is, the equivalent of oncogene addiction), thus portending the clinical use of EZH2 inhibitors for cancers in which EZH2 is genetically altered.
EZH2 催化组蛋白 H3 赖氨酸 27（H3K27）的三甲基化。EZH2 在 Tyr641 和 Ala677 处的点突变发生在非霍奇金淋巴瘤的亚群中，它们驱动 H3K27 超甲基化。在这里，我们报告了 EPZ005687 的发现，它是一种有效的 EZH2 抑制剂（K(i)为 24 nM）。EPZ005687 对 15 种其他蛋白质甲基转移酶具有超过 500 倍的选择性，对密切相关的酶 EZH1 具有 50 倍的选择性。该化合物减少各种淋巴瘤细胞中的 H3K27 甲基化; 这会导致杂合 Tyr641 或 Ala677 突变细胞发生凋亡性细胞杀伤，而对野生型细胞的增殖影响最小。这些数据表明，EZH2 的遗传改变（例如，Tyr641 或 Ala677 处的突变）导致对增殖的酶活性的关键依赖性（即，相当于致癌基因成瘾），从而预示着 EZH2 抑制剂在其中 EZH2 发生遗传改变的癌症中的临床应用。
