State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.
School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
J Med Chem. 2021 Mar 11;64(5):2829-2848. doi: 10.1021/acs.jmedchem.0c02234. Epub 2021 Feb 19.
EZH2 mediates both PRC2-dependent gene silencing via catalyzing H3K27me3 and PRC2-independent transcriptional activation in various cancers. Given its oncogenic role in cancers, EZH2 has constituted a compelling target for anticancer therapy. However, current EZH2 inhibitors only target its methyltransferase activity to downregulate H3K27me3 levels and show limited efficacy because of inadequate suppression of the EZH2 oncogenic activity. Therefore, therapeutic strategies to completely block the oncogenic activity of EZH2 are urgently needed. Herein, we report a series of EZH2-targeted proteolysis targeting chimeras (PROTACs) that induce proteasomal degradation of PRC2 components, including EZH2, EED, SUZ12, and RbAp48. Preliminary assessment identified as the most active PROTAC molecule, which decreased PRC2 subunits and H3K27me2/3 levels in various cancer cells. Furthermore, strongly inhibited transcriptional silencing mediated by EZH2 dependent on PRC2 and transcriptional activation mediated by EZH2 independent of PRC2, showing significant antiproliferative activities against cancer cell lines dependent on the enzymatic and nonenzymatic activities of EZH2.
EZH2 通过催化 H3K27me3 介导 PRC2 依赖性基因沉默，并在各种癌症中发挥 PRC2 非依赖性转录激活作用。鉴于其在癌症中的致癌作用，EZH2 已成为癌症治疗的一个有吸引力的靶点。然而，目前的 EZH2 抑制剂仅靶向其甲基转移酶活性，以下调 H3K27me3 水平，由于对 EZH2 致癌活性的抑制不足，显示出有限的疗效。因此，迫切需要能够完全阻断 EZH2 致癌活性的治疗策略。本文报道了一系列 EZH2 靶向的蛋白水解靶向嵌合体（PROTACs），可诱导 PRC2 成分（包括 EZH2、EED、SUZ12 和 RbAp48）的蛋白酶体降解。初步评估确定 为最有效的 PROTAC 分子，其降低了各种癌细胞中 PRC2 亚基和 H3K27me2/3 水平。此外， 强烈抑制了依赖 PRC2 的 EZH2 介导的转录沉默和不依赖 PRC2 的 EZH2 介导的转录激活，对依赖 EZH2 酶活性和非酶活性的癌细胞系显示出显著的抗增殖活性。
