Degradation of Polycomb Repressive Complex 2 with an EED-Targeted Bivalent Chemical Degrader.
Cell Chem Biol
; 27(1): 47-56.e15, 2020 01 16.
Article
en En
| MEDLINE
| ID: mdl-31831267
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.
Palabras clave
Proteolysis-Targeting Chimera (PROTAC); bivalent chemical degrader; diffuse large B cell lymphoma (DLBCL); embryonic ectoderm development (EED); enhancer of zeste homolog 2 (EZH2); histone methyltransferase (HMT); polycomb repressive complex 2 (PRC2); suppressor of zeste homolog 12 (SUZ12); von Hippel-Lindau (VHL)
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Inhibidores Enzimáticos
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Proteolisis
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Complejo Represivo Polycomb 2
Límite:
Humans
Idioma:
En
Revista:
Cell Chem Biol
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
EEUU
/
ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
/
EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
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USA