EED-Targeted PROTACs Degrade EED, EZH2, and SUZ12 in the PRC2 Complex
| Autor: | Sameer Kawatkar, Philip B. Rawlins, Ning Gao, S. Bagal, Ronald Tomlinson, David Matthew Wilson, Elisabetta Chiarparin, James Robinson, Jessie Hao-Ru Hsu, Erin Code, Emma Bednarski, Lisa Drew, Kelly Jacques, Stephen Fawell, Andrew Bloecher, Xiahui Zhu, M. Paola Castaldi, Timothy Rasmusson, Haley Woods, Jon Read, Argyrides Argyrou, Minhui Shen, Daniel H. O' Donovan, Fiona Pachl |
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| Rok vydání: | 2020 |
| Předmět: |
Pharmacology
biology 010405 organic chemistry Clinical Biochemistry EZH2 Druggability macromolecular substances 01 natural sciences Biochemistry 0104 chemical sciences Cell biology Ubiquitin ligase chemistry.chemical_compound chemistry Drug Discovery Cancer cell biology.protein SUZ12 Molecular Medicine Growth inhibition PRC2 Molecular Biology Ternary complex |
| Zdroj: | Cell Chemical Biology. 27:41-46.e17 |
| ISSN: | 2451-9456 |
| DOI: | 10.1016/j.chembiol.2019.11.004 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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