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.

中文翻译：

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发现一流的 G9a/GLP PROTAC 降解器

异常表达的赖氨酸甲基转移酶 G9a 和 GLP 可催化组蛋白 H3 赖氨酸 9 (H3K9) 的单甲基化和二甲基化，与多种癌症有关。最近的研究揭示了 G9a/GLP 的催化和非催化致癌功能。因此，G9a/GLP 催化抑制剂表现出有限的抗癌活性。在这里，我们报告了一流的 G9a/GLP 蛋白水解靶向嵌合体 (PROTAC) 降解剂10 (MS8709) 的发现，作为一种潜在的抗癌疗法。10以浓度、时间和泛素蛋白酶体系统 (UPS) 依赖性方式诱导 G9a/GLP 降解。此外，10不会改变 G9a/GLP 的 mRNA 表达，并且对 G9a/GLP 的选择性高于其他甲基转移酶。此外，10在前列腺、白血病和肺癌细胞中表现出优于母体 G9a/GLP 抑制剂 UNC0642 的细胞生长抑制作用，并具有适合体内功效研究的小鼠药代动力学特性。总体而言，10是一种有价值的化学生物学工具，可进一步研究 G9a/GLP 的功能，也是治疗 G9a/GLP 依赖性癌症的潜在疗法。