EED-Targeted PROTACs Degrade EED, EZH2, and SUZ12 in the PRC2 Complex
Open accessAbstract
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 ∼ 9.0) and promote ternary complex formation with the E3 ubiquitin ligase. The PROTACs potently inhibit PRC2 enzyme activity (pIC 50 ∼ 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.
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Proteins that are not directly bound to a PROTAC can be degraded if they are part of the same complex or are in close proximity with the target protein.
“For example, proteins that are not directly bound to a PROTAC can be degraded if they are a part of the same complex or are in close proximity with the target protein [161].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [161]
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- Authors
- Hsu, J. H.-R., Rasmusson, T., Robinson, J., Pachl, F., Read, J., Kawatkar, S., O’ Donovan, D. H., Bagal, S., Code, E., Rawlins, P., Argyrou, A., Tomlinson, R., Gao, N., Zhu, X., Chiarparin, E., Jacques, K., Shen, M., Woods, H., Bednarski, E., Wilson, D. M., Drew, L., Castaldi, M. P., Fawell, S., & Bloecher, A.
- Affiliations
- AstraZeneca (United States) (US)
- AstraZeneca (United Kingdom) (GB)
- Corresponding author
- Bloecher, Andrew
- ORCID
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2020-01
- Volume
- 27
- Issue
- 1
- Pages
- 41-46.e17
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- OpenAlex
- W2991059836
- Cited by
- 202
- References
- 20
- Citations by year
- 2026: 14 · 2025: 20 · 2024: 39 · 2023: 37 · 2022: 34 · 2021: 36 · 2020: 21 · 2019: 1
- FWCI
- 7.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell chemical biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- AstraZeneca
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- PROTACs, EED, EZH2, SUZ12, polycomb repressive complex 2, H3K27 methylation, protein degradation, E3 ubiquitin ligase, cancer therapy, heterobifunctional molecules
- MeSH terms
- Dose-Response Relationship, Drug, Enzyme Inhibitors, Humans, Structure-Activity Relationship, Molecular Structure, Cell Line, Tumor, Cell Proliferation, Proteolysis, Polycomb Repressive Complex 2
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