2. Academic Validation
  3. Discovery of a first-in-class EZH2 selective degrader

Discovery of a first-in-class EZH2 selective degrader

  • Nat Chem Biol. 2020 Feb;16(2):214-222. doi: 10.1038/s41589-019-0421-4.
Anqi Ma  # 1,  Elias Stratikopoulos  # 2,  Kwang-Su Park  # 1,  Jieli Wei 1,  Tiphaine C Martin 2,  Xiaobao Yang 1,  Megan Schwarz 2,  Violetta Leshchenko 3,  Alexander Rialdi 2,  Brandon Dale 1,  Alessandro Lagana 4,  Ernesto Guccione 1 2,  Samir Parekh 2 3,  Ramon Parsons 5,  Jian Jin 6 7
Affiliations

Affiliations

  • 1 Mount Sinai Center for Therapeutics Discovery, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 2 Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 3 Division of Hematology and Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 4 Department of Genetics and Genomic Sciences, Institute for Next Generation Healthcare, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 5 Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ramon.parsons@mssm.edu.
  • 6 Mount Sinai Center for Therapeutics Discovery, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. jian.jin@mssm.edu.
  • 7 Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. jian.jin@mssm.edu.
  • # Contributed equally.
PMID: 31819273 DOI: 10.1038/s41589-019-0421-4
Abstract

The enhancer of zeste homolog 2 (EZH2) is the main enzymatic subunit of the PRC2 complex, which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) to promote transcriptional silencing. EZH2 is overexpressed in multiple types of Cancer including triple-negative breast Cancer (TNBC), and high expression levels correlate with poor prognosis. Several EZH2 inhibitors, which inhibit the methyltransferase activity of EZH2, have shown promise in treating sarcoma and follicular lymphoma in clinics. However, EZH2 inhibitors are ineffective at blocking proliferation of TNBC cells, even though they effectively reduce the H3K27me3 mark. Using a hydrophobic tagging approach, we generated MS1943, a first-in-class EZH2 selective degrader that effectively reduces EZH2 levels in cells. Importantly, MS1943 has a profound cytotoxic effect in multiple TNBC cells, while sparing normal cells, and is efficacious in vivo, suggesting that pharmacologic degradation of EZH2 can be advantageous for treating the cancers that are dependent on EZH2.

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