puc-header

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

98 Pages Posted: 1 Jul 2019 Sneak Peek Status: Published

See all articles by Frances Potjewyd

Frances Potjewyd

University of North Carolina (UNC) at Chapel Hill - Center for Integrative Chemical Biology and Drug Discovery

Anne-Marie Turner

University of North Carolina (UNC) at Chapel Hill

Joshua Beri

University of North Carolina (UNC) at Chapel Hill

Justin Rectenwald

University of North Carolina (UNC) at Chapel Hill - Center for Integrative Chemical Biology and Drug Discovery

Jacqueline Norris-Drouin

University of North Carolina (UNC) at Chapel Hill - Center for Integrative Chemical Biology and Drug Discovery

Stephanie Cholensky

University of North Carolina (UNC) at Chapel Hill - Center for Integrative Chemical Biology and Drug Discovery

David M. Margolis

University of North Carolina (UNC) at Chapel Hill

Kenneth Pearce

University of North Carolina (UNC) at Chapel Hill - Center for Integrative Chemical Biology and Drug Discovery

Laura Herring

University of North Carolina (UNC) at Chapel Hill

Lindsey Ingerman James

University of North Carolina (UNC) at Chapel Hill - Center for Integrative Chemical Biology and Drug Discovery

More...

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. Herein we report a first-in-class 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 an EZH2Y641N gain-of-function mutation. UNC6852 degrades both wild type EZH2 and EZH2Y641N, and additionally displays anti-proliferative effects in this cancer model system.

Keywords: Embryonic Ectoderm Development (EED), Enhancer of Zeste Homolog 2 (EZH2), Suppressor of Zeste Homolog 12 (SUZ12), Polycomb Repressive Complex 2 (PRC2), bivalent chemical degrader, von-Hippel Lindau (VHL), diffuse large B-cell lymphoma (DLBCL), histone methyltransferase (HMT)

Suggested Citation

Potjewyd, Frances and Turner, Anne-Marie and Beri, Joshua and Rectenwald, Justin and Norris-Drouin, Jacqueline and Cholensky, Stephanie and Margolis, David M. and Pearce, Kenneth and Herring, Laura and James, Lindsey Ingerman, Degradation of Polycomb Repressive Complex 2 with an EED-Targeted Bivalent Chemical Degrader (July 1, 2019). Available at SSRN: https://ssrn.com/abstract=3413103 or http://dx.doi.org/10.2139/ssrn.3413103
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Frances Potjewyd

University of North Carolina (UNC) at Chapel Hill - Center for Integrative Chemical Biology and Drug Discovery

102 Ridge Road
Chapel Hill, NC 27514
United States

Anne-Marie Turner

University of North Carolina (UNC) at Chapel Hill

102 Ridge Road
Chapel Hill, NC NC 27514
United States

Joshua Beri

University of North Carolina (UNC) at Chapel Hill

102 Ridge Road
Chapel Hill, NC NC 27514
United States

Justin Rectenwald

University of North Carolina (UNC) at Chapel Hill - Center for Integrative Chemical Biology and Drug Discovery

102 Ridge Road
Chapel Hill, NC 27514
United States

Jacqueline Norris-Drouin

University of North Carolina (UNC) at Chapel Hill - Center for Integrative Chemical Biology and Drug Discovery

102 Ridge Road
Chapel Hill, NC 27514
United States

Stephanie Cholensky

University of North Carolina (UNC) at Chapel Hill - Center for Integrative Chemical Biology and Drug Discovery

102 Ridge Road
Chapel Hill, NC 27514
United States

David M. Margolis

University of North Carolina (UNC) at Chapel Hill

102 Ridge Road
Chapel Hill, NC NC 27514
United States

Kenneth Pearce

University of North Carolina (UNC) at Chapel Hill - Center for Integrative Chemical Biology and Drug Discovery

102 Ridge Road
Chapel Hill, NC 27514
United States

Laura Herring

University of North Carolina (UNC) at Chapel Hill

102 Ridge Road
Chapel Hill, NC NC 27514
United States

Lindsey Ingerman James (Contact Author)

University of North Carolina (UNC) at Chapel Hill - Center for Integrative Chemical Biology and Drug Discovery ( email )

102 Ridge Road
Chapel Hill, NC 27514
United States

Click here to go to Cell.com

Paper statistics

Abstract Views
293
Downloads
6