Deregulation of the PRC2 complex, comprised of the core subunits EZH2, SUZ12, and EED, drives aberrant hypermethylation of H3K27 and tumorigenicity of many cancers. Although inhibitors of EZH2 have shown promising clinical activity, preclinical data suggest that resistance can be acquired through secondary mutations in EZH2 that abrogate drug target engagement. To address these limitations, we have designed several hetero-bifunctional PROTACs (proteolysis-targeting chimera) to efficiently target EED for elimination. Our PROTACs bind to EED (pKD ∼ 9.0) and promote ternary complex formation with the E3 ubiquitin ligase. The PROTACs potently inhibit PRC2 enzyme activity (pIC50 ∼ 8.1) and induce rapid degradation of not only EED but also EZH2 and SUZ12 within the PRC2 complex. Furthermore, the PROTACs selectively inhibit proliferation of PRC2-dependent cancer cells (half maximal growth inhibition [GI50] = 49-58 nM). In summary, our data demonstrate a therapeutic modality to target PRC2-dependent cancer through a PROTAC-mediated degradation mechanism.

中文翻译：

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针对EED的PROTAC会降低PRC2大楼中的EED，EZH2和SUZ12。

由核心亚基EZH2，SUZ12和EED组成的PRC2复合物的失控驱动H3K27的异常高甲基化和许多癌症的致癌性。尽管EZH2抑制剂显示出令人鼓舞的临床活性，但临床前数据表明，可以通过消除药物靶点参与的EZH2继发突变获得耐药性。为了解决这些局限性，我们设计了几种异双功能的PROTAC（靶向蛋白水解的嵌合体）来有效靶向消除EED。我们的PROTAC与EED结合（pKD〜9.0），并与E3泛素连接酶一起促进三元复合物的形成。PROTAC有效抑制PRC2酶的活性（pIC50〜8.1），并引起PRC2复合物中的EED以及EZH2和SUZ12迅速降解。此外，PROTAC选择性抑制PRC2依赖性癌细胞的增殖（最大最大抑制一半[GI50] = 49-58 nM）。总而言之，我们的数据证明了通过PROTAC介导的降解机制靶向PRC2依赖性癌症的治疗方法。