Degradation of Polycomb Repressive Complex 2 with an EED-Targeted Bivalent Chemical Degrader.

Cell Line, Tumor Enzyme Inhibitors / chemistry HeLa Cells Humans Ligands Molecular Structure Polycomb Repressive Complex 2 / metabolism Proteolysis / drug effects
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)

Journal

Cell chemical biology
ISSN: 2451-9448
Titre abrégé: Cell Chem Biol
Pays: United States
ID NLM: 101676030

Informations de publication

Date de publication:
16 01 2020
Historique:
received: 19 06 2019
revised: 04 10 2019
accepted: 12 11 2019
pubmed: 14 12 2019
medline: 16 3 2021
entrez: 14 12 2019
Statut: ppublish

Résumé

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 CRL2

Identifiants

DOI: 10.1016/j.chembiol.2019.11.006 PMID: 31831267 PMC: PMC7004250
pubmed: 31831267
pii: S2451-9456(19)30364-2
doi: 10.1016/j.chembiol.2019.11.006
pmc: PMC7004250
mid: NIHMS1060083
pii:
doi:

Substances chimiques

Enzyme Inhibitors 0
Ligands 0
Polycomb Repressive Complex 2 EC 2.1.1.43

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

47-56.e15

Subventions

Organisme : NCI NIH HHS
ID : P30 CA016086
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM100919
Pays : United States
Organisme : NIDA NIH HHS
ID : R61 DA047023
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008570
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2019 Elsevier Ltd. All rights reserved.

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Auteurs

Frances Potjewyd (F)

Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Anne-Marie W Turner (AW)

UNC HIV Cure Center, Institute of Global Health and Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Joshua Beri (J)

UNC Proteomics Core Facility, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Justin M Rectenwald (JM)

Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Jacqueline L Norris-Drouin (JL)

Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Stephanie H Cholensky (SH)

Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

David M Margolis (DM)

UNC HIV Cure Center, Institute of Global Health and Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Medicine, School Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Kenneth H Pearce (KH)

Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Laura E Herring (LE)

UNC Proteomics Core Facility, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Lindsey I James (LI)

Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: ingerman@email.unc.edu.

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Classifications MeSH

questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Degradation of Polycomb Repressive Complex 2...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Degradation of Polycomb Repressive Complex 2...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HeLa › Degradation of Polycomb Repressive Complex 2...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Degradation of Polycomb Repressive Complex 2...
questionsmedicales.fr › Actions chimiques et utilisations › Utilisations spécialisées de produits chimiques › Produits chimiques de laboratoire › Ligands › Degradation of Polycomb Repressive Complex 2...
questionsmedicales.fr › Phénomènes chimiques › Structure moléculaire › Degradation of Polycomb Repressive Complex 2...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Protéines de répression › Protéines du groupe Polycomb › Complexe répresseur Polycomb-2 › Degradation of Polycomb Repressive Complex 2...
questionsmedicales.fr › Métabolisme › Protéolyse › Degradation of Polycomb Repressive Complex 2...