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

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.

中文翻译:


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



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。
更新日期:2024-01-26
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