<br>发现一种新型高效 EZH2 PROTAC 降解剂，用于靶向 EZH2 的非典型致癌功能,European Journal of Medicinal Chemistry

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发现一种新型高效 EZH2 PROTAC 降解剂，用于靶向 EZH2 的非典型致癌功能
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2024-01-26 , DOI: 10.1016/j.ejmech.2024.116154
Julia Velez ₁ , Brandon Dale ₁ , Kwang-Su Park ₁ , H Ümit Kaniskan ₁ , Xufen Yu ₁ , Jian Jin ₁

Affiliation

EZH2（PRC2 的主要催化亚基）的异常表达与多种癌症有关，包括白血病、乳腺癌和前列腺癌。最近的研究强调了 EZH2 的非催化致癌功能，EZH2 催化抑制剂无法减弱这种功能。因此，蛋白水解靶向嵌合体（PROTAC）降解剂已被探索作为抑制典型和非典型致癌活性的替代治疗方法。在此，我们推出 MS8847，这是一种新型高效 EZH2 PROTAC 降解剂，可招募 E3 连接酶 von Hippel-Lindau (VHL)。 MS8847 以浓度、时间和泛素蛋白酶体系统 (UPS) 依赖性方式降解 EZH2。值得注意的是，与之前发表的 EZH2 PROTAC 降解剂相比，MS8847 在 MLL 重排 (MLL-r) 急性髓系白血病 (AML) 细胞中诱导出优异的 EZH2 降解和抗增殖作用。此外，MS8847 可降解 EZH2 并抑制三阴性乳腺癌 (TNBC) 细胞系中的细胞生长，在 3D TNBC 体外模型中显示出功效，并具有适合体内功效研究的药代动力学 (PK) 特征。总体而言，MS8847 是生物医学界研究 EZH2 典型和非典型致癌功能的宝贵化学工具。

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Discovery of a novel, highly potent EZH2 PROTAC degrader for targeting non-canonical oncogenic functions of EZH2

Aberrant expression of EZH2, the main catalytic subunit of PRC2, has been implicated in numerous cancers, including leukemia, breast, and prostate. Recent studies have highlighted non-catalytic oncogenic functions of EZH2, which EZH2 catalytic inhibitors cannot attenuate. Therefore, proteolysis-targeting chimera (PROTAC) degraders have been explored as an alternative therapeutic approach to suppress both canonical and non-canonical oncogenic activity. Here we present MS8847, a novel, highly potent EZH2 PROTAC degrader that recruits the E3 ligase von Hippel-Lindau (VHL). MS8847 degrades EZH2 in a concentration-, time-, and ubiquitin–proteasome system (UPS)-dependent manner. Notably, MS8847 induces superior EZH2 degradation and anti-proliferative effects in MLL-rearranged (MLL-r) acute myeloid leukemia (AML) cells compared to previously published EZH2 PROTAC degraders. Moreover, MS8847 degrades EZH2 and inhibits cell growth in triple-negative breast cancer (TNBC) cell lines, displays efficacy in a 3D TNBC in vitro model, and has a pharmacokinetic (PK) profile suitable for in vivo efficacy studies. Overall, MS8847 is a valuable chemical tool for the biomedical community to investigate canonical and non-canonical oncogenic functions of EZH2.

更新日期：2024-01-26

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