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Published on: November 9, 2020
Design and Synthesis of EZH2-Based PROTACs to Degrade the PRC2 Complex for Targeting the Noncatalytic Activity of
Zhihao Liu1, Xi Hu1, Qiwei Wang1
1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.
Abstract:
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.
Insights
New PROTACs target EZH2 protein degradation, not just its activity. The lead molecule E7 effectively reduced cancer cell proliferation by inhibiting both PRC2-dependent and independent EZH2 functions.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Enhancer of Zeste Homolog 2 (EZH2) drives cancer through gene silencing and activation.
- Current EZH2 inhibitors targeting methyltransferase activity show limited efficacy.
- Novel strategies are needed to fully inhibit EZH2's oncogenic functions.
Purpose of the Study:
- To develop novel EZH2-targeted proteolysis targeting chimeras (PROTACs).
- To induce proteasomal degradation of Polycomb Repressive Complex 2 (PRC2) components.
- To evaluate the efficacy of E7 PROTAC in inhibiting EZH2's dual functions and cancer cell proliferation.
Main Methods:
- Design and synthesis of EZH2-targeted PROTACs.
- Assessment of PROTACs' ability to degrade PRC2 subunits (EZH2, EED, SUZ12, RbAp48).
- Evaluation of E7's impact on H3K27me2/3 levels, gene expression, and cancer cell proliferation.
Main Results:
- Identified E7 as a potent PROTAC molecule inducing degradation of PRC2 components.
- E7 decreased H3K27me2/3 levels in cancer cells.
- E7 inhibited both PRC2-dependent silencing and PRC2-independent activation mediated by EZH2.
- E7 demonstrated significant antiproliferative activity against cancer cell lines.
Conclusions:
- EZH2-targeted PROTACs offer a promising therapeutic strategy by inducing protein degradation.
- E7 effectively inhibits both enzymatic and non-enzymatic oncogenic activities of EZH2.
- Targeting EZH2 degradation represents a potential breakthrough in cancer therapy.
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