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

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

  • Cell Chem Biol. 2020 Jan 16;27(1):47-56.e15. doi: 10.1016/j.chembiol.2019.11.006.
Frances Potjewyd 1,  Anne-Marie W Turner 2,  Joshua Beri 3,  Justin M Rectenwald 4,  Jacqueline L Norris-Drouin 1,  Stephanie H Cholensky 1,  David M Margolis 5,  Kenneth H Pearce 1,  Laura E Herring 3,  Lindsey I James 6
Affiliations

Affiliations

  • 1 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.
  • 2 UNC HIV Cure Center, Institute of Global Health and Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 3 UNC Proteomics Core Facility, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 4 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.
  • 5 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.
  • 6 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.
PMID: 31831267 DOI: 10.1016/j.chembiol.2019.11.006
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.

Keywords

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).

Figures
Products