2. Academic Validation
  3. EED-Targeted PROTACs Degrade EED, EZH2, and SUZ12 in the PRC2 Complex

EED-Targeted PROTACs Degrade EED, EZH2, and SUZ12 in the PRC2 Complex

  • Cell Chem Biol. 2020 Jan 16;27(1):41-46.e17. doi: 10.1016/j.chembiol.2019.11.004.
Jessie Hao-Ru Hsu 1,  Timothy Rasmusson 2,  James Robinson 3,  Fiona Pachl 2,  Jon Read 3,  Sameer Kawatkar 1,  Daniel H O' Donovan 4,  Sharan Bagal 4,  Erin Code 2,  Philip Rawlins 3,  Argyrides Argyrou 3,  Ronald Tomlinson 2,  Ning Gao 2,  Xiahui Zhu 2,  Elisabetta Chiarparin 4,  Kelly Jacques 1,  Minhui Shen 1,  Haley Woods 1,  Emma Bednarski 1,  David M Wilson 4,  Lisa Drew 1,  M Paola Castaldi 2,  Stephen Fawell 1,  Andrew Bloecher 5
Affiliations

Affiliations

  • 1 Oncology R&D, AstraZeneca, Waltham, MA 02451, USA.
  • 2 Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA 02451, USA.
  • 3 Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB4 0FZ, UK.
  • 4 Oncology R&D, AstraZeneca, Cambridge CB4 0FZ, UK.
  • 5 Oncology R&D, AstraZeneca, Waltham, MA 02451, USA. Electronic address: andrew.bloecher@astrazeneca.com.
PMID: 31786184 DOI: 10.1016/j.chembiol.2019.11.004
Abstract

Deregulation of the PRC2 complex, comprised of the core subunits EZH2, SUZ12, and EED, drives aberrant hypermethylation of H3K27 and tumorigenicity of many cancers. Although inhibitors of EZH2 have shown promising clinical activity, preclinical data suggest that resistance can be acquired through secondary mutations in EZH2 that abrogate drug target engagement. To address these limitations, we have designed several hetero-bifunctional PROTACs (proteolysis-targeting chimera) to efficiently target EED for elimination. Our PROTACs bind to EED (pKD ∼ 9.0) and promote ternary complex formation with the E3 ubiquitin Ligase. The PROTACs potently inhibit PRC2 Enzyme activity (pIC50 ∼ 8.1) and induce rapid degradation of not only EED but also EZH2 and SUZ12 within the PRC2 complex. Furthermore, the PROTACs selectively inhibit proliferation of PRC2-dependent Cancer cells (half maximal growth inhibition [GI50] = 49-58 nM). In summary, our data demonstrate a therapeutic modality to target PRC2-dependent Cancer through a PROTAC-mediated degradation mechanism.

Keywords

EED; EZH2; SUZ12; druggability; polycomb repressive complex 2 (PRC2); proteolysis targeting chimeras (PROTACs); ubiquitin-mediated protein degradation.

Figures
Products