EED-Targeted PROTACs Degrade EED, EZH2, and SUZ12 in the PRC2 Complex
EED-Targeted PROTACs Degrade EED, EZH2, and SUZ12 in the PRC2 Complex
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DOI：
10.1016/j.chembiol.2019.11.004
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发表时间：
2020-01-16
影响因子：
8.6
通讯作者：
Bloecher, Andrew
中科院分区：
文献类型：
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作者：
Hsu, Jessie Hao-Ru;Rasmusson, Timothy;Bloecher, Andrew
由核心亚基EZH2、SUZ12和EED组成的PRC2复合体的解除调控可驱动H3K27的异常高甲基化和许多癌症的致瘤性。尽管EZH2抑制剂已显示出良好的临床活性，但临床前数据表明，EZH2的继发性突变可使药物靶向作用失效，从而获得耐药性。为了解决这些限制，我们设计了几个异双功能PROTACs（蛋白水解靶向嵌合体）来有效地靶向EED以消除。我们的PROTACs与EED结合（pK(D)类似于9.0），并促进与E3泛素连接酶形成三元复合物。PROTACs能有效抑制PRC2酶活性（pIC（50）与8.1相似），并诱导PRC2复合物内EED、EZH2和SUZ12的快速降解。此外，PROTACs选择性地抑制prc2依赖性癌细胞的增殖（一半最大生长抑制[GI(50)] = 49-58 nM）。总之，我们的数据证明了一种通过protac介导的降解机制靶向prc2依赖性癌症的治疗模式。
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 (pK(D) similar to 9.0) and promote ternary complex formation with the E3 ubiquitin ligase. The PROTACs potently inhibit PRC2 enzyme activity (pIC(50) similar to 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 [GI(50)] = 49-58 nM). In summary, our data demonstrate a therapeutic modality to target PRC2-dependent cancer through a PROTAC-mediated degradation mechanism.