Degradation of Polycomb Repressive Complex 2 with an EED-Targeted Bivalent Chemical Degrader
Public Deposited- Creator
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Potjewyd, F.
- Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery
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Turner, A.-M.W.
- HIV Cure Center
- Beri, J.
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Rectenwald, J.M.
- Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery
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Norris-Drouin, J.L.
- Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery
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Cholensky, S.H.
- Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery
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Margolis, D.M.
- HIV Cure Center
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Pearce, K.H.
- Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery
- Herring, L.E.
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James, L.I.
- Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery
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Potjewyd, F.
- Abstract
- Protein degradation via the use of bivalent chemical degraders provides an alternative strategy to block protein function and assess the biological roles of putative drug targets. This approach capitalizes on the advantages of small-molecule inhibitors while moving beyond the restrictions of traditional pharmacology. Here, we report a chemical degrader (UNC6852) that targets polycomb repressive complex 2 (PRC2). UNC6852 contains an EED226-derived ligand and a ligand for VHL which bind to the WD40 aromatic cage of EED and CRL2VHL, respectively, to induce proteasomal degradation of PRC2 components, EED, EZH2, and SUZ12. Degradation of PRC2 with UNC6852 blocks the histone methyltransferase activity of EZH2, decreasing H3K27me3 levels in HeLa cells and diffuse large B cell lymphoma (DLBCL) cells containing EZH2 gain-of-function mutations. UNC6852 degrades both wild-type and mutant EZH2, and additionally displays anti-proliferative effects in this cancer model system. Using an EED-targeted chemical degrader, Potjewyd et al. demonstrate successful degradation of the PRC2 complex. UNC6852 provides a unique tool to study PRC2 function and downregulation of PRC2 activity in cancer and demonstrates the feasibility of developing PRC2-targeted degraders as potential therapeutics.
- Date of publication
- 2020
- Keyword
- polycomb repressive complex 2 (PRC2)
- diffuse large B cell lymphoma (DLBCL)
- histone methyltransferase (HMT)
- embryonic ectoderm development (EED)
- enhancer of zeste homolog 2 (EZH2)
- bivalent chemical degrader
- von Hippel-Lindau (VHL)
- suppressor of zeste homolog 12 (SUZ12)
- Proteolysis-Targeting Chimera (PROTAC)
- DOI
- Identifier
- PMID 31831267
- https://dx.doi.org/10.1016/j.chembiol.2019.11.006
- Resource type
- Article
- Rights statement
- In Copyright
- Journal title
- Cell Chemical Biology
- Journal volume
- 27
- Journal issue
- 1
- Page start
- 47
- Page end
- 56.e15
- Language
- English
- ISSN
- 2451-9456
- Publisher
- Elsevier Ltd
Relations
- Parents:
This work has no parents.
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