Design and Synthesis of EZH2-Based PROTACs to Degrade the PRC2 Complex for Targeting the Noncatalytic Activity of EZH2
| Autor: | Yongxia Zhu, Rong Hu, Tinghong Ye, Xiuli Wu, Wei Wei, Hualong He, Luoting Yu, Xi Hu, Qi-Wei Wang, Zhihao Liu, Ning-Yu Wang, Xingping Su, Shu-Yan Zhou, Qiangsheng Zhang |
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| Rok vydání: | 2021 |
| Předmět: |
Methyltransferase
Ubiquitin-Protein Ligases Proteolysis Antineoplastic Agents Phthalimides macromolecular substances 01 natural sciences 03 medical and health sciences Downregulation and upregulation Cell Line Tumor Drug Discovery medicine SUZ12 Humans Gene silencing Enhancer of Zeste Homolog 2 Protein Adaptor Proteins Signal Transducing Cell Proliferation 030304 developmental biology 0303 health sciences medicine.diagnostic_test biology Chemistry EZH2 Ubiquitination 0104 chemical sciences Cell biology 010404 medicinal & biomolecular chemistry Drug Design Benzamides Cancer cell biology.protein Molecular Medicine Drug Screening Assays Antitumor PRC2 |
| Zdroj: | Journal of Medicinal Chemistry. 64:2829-2848 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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 E7 as the most active PROTAC molecule, which decreased PRC2 subunits and H3K27me2/3 levels in various cancer cells. Furthermore, E7 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. |
| Databáze: | OpenAIRE |
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