Discovery of a first-in-class EZH2 selective degrader.,Nature Chemical Biology

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Discovery of a first-in-class EZH2 selective degrader.
Nature Chemical Biology ( IF 12.9 ) Pub Date : 2019-12-09 , DOI: 10.1038/s41589-019-0421-4
Anqi Ma ₁ , Elias Stratikopoulos ₂ , Kwang-Su Park ₁ , Jieli Wei ₁ , Tiphaine C Martin ₂ , Xiaobao Yang ₁ , Megan Schwarz ₂ , Violetta Leshchenko ₃ , Alexander Rialdi ₂ , Brandon Dale ₁ , Alessandro Lagana ₄ , Ernesto Guccione _{1,

2} , Samir Parekh _{2,

3} , Ramon Parsons ₂ , Jian Jin _{1,

2}

Affiliation

The enhancer of zeste homolog 2 (EZH2) is the main enzymatic subunit of the PRC2 complex, which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) to promote transcriptional silencing. EZH2 is overexpressed in multiple types of cancer including triple-negative breast cancer (TNBC), and high expression levels correlate with poor prognosis. Several EZH2 inhibitors, which inhibit the methyltransferase activity of EZH2, have shown promise in treating sarcoma and follicular lymphoma in clinics. However, EZH2 inhibitors are ineffective at blocking proliferation of TNBC cells, even though they effectively reduce the H3K27me3 mark. Using a hydrophobic tagging approach, we generated MS1943, a first-in-class EZH2 selective degrader that effectively reduces EZH2 levels in cells. Importantly, MS1943 has a profound cytotoxic effect in multiple TNBC cells, while sparing normal cells, and is efficacious in vivo, suggesting that pharmacologic degradation of EZH2 can be advantageous for treating the cancers that are dependent on EZH2.

中文翻译：

发现一流的 EZH2 选择性降解剂。

zeste 同源物 2 (EZH2) 的增强子是 PRC2 复合物的主要酶亚基，它催化组蛋白 H3 赖氨酸 27 (H3K27me3) 的三甲基化以促进转录沉默。 EZH2 在包括三阴性乳腺癌 (TNBC) 在内的多种癌症中过度表达，高表达水平与不良预后相关。几种抑制 EZH2 甲基转移酶活性的 EZH2 抑制剂已在临床治疗肉瘤和滤泡性淋巴瘤方面显示出前景。然而，EZH2 抑制剂无法有效阻止 TNBC 细胞的增殖，尽管它们可以有效降低 H3K27me3 标记。使用疏水标记方法，我们生成了 MS1943，这是一种一流的 EZH2 选择性降解剂，可有效降低细胞中的 EZH2 水平。重要的是，MS1943 对多种 TNBC 细胞具有深远的细胞毒性作用，同时不影响正常细胞，并且在体内有效，这表明 EZH2 的药理降解可能有利于治疗依赖 EZH2 的癌症。

更新日期：2019-12-11

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