Targeting Triple-Negative Breast Cancer by a Novel Proteolysis Targeting Chimera Degrader of Enhancer of Zeste Homolog 2

Brandon Dale, Chris Anderson, Kwang Su Park, H. Ümit Kaniskan, Anqi Ma, Yudao Shen, Chengwei Zhang, Ling Xie, Xian Chen, Xufen Yu, Jian Jin

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Enhancer of zeste homolog 2 (EZH2), a catalytic subunit of polycomb repressive complex 2 (PRC2), is overexpressed in triple-negative breast cancer (TNBC), correlating with poor prognosis. However, EZH2 catalytic inhibitors are ineffective in suppressing the growth of TNBC cells that are dependent on EZH2. Knockdown of EZH2 inhibits the proliferation of these cells, suggesting that EZH2 protein overexpression but not its catalytic activity is critical for driving TNBC progression. Several proteolysis targeting chimera (PROTAC) degraders of EZH2, including the von Hippel-Lindau (VHL)-recruiting PROTAC YM281, have been reported. However, the effects of these EZH2 PROTACs in TNBC cells were not investigated. Here, we report the discovery and characterization of a novel, potent, and selective EZH2 PROTAC degrader, MS8815 (compound 16), which induced robust EZH2 degradation in a concentration-, time-, and proteasome-dependent manner in TNBC cells. Importantly, 16 effectively suppressed the cell growth in multiple TNBC cell lines and primary patient TNBC cells.

Original languageEnglish
Pages (from-to)491-507
Number of pages17
JournalACS Pharmacology and Translational Science
Volume5
Issue number7
DOIs
StatePublished - 8 Jul 2022

Keywords

  • EZH2
  • PROTAC
  • cancer treatment
  • epigenetics
  • triple-negative breast cancer

Fingerprint

Dive into the research topics of 'Targeting Triple-Negative Breast Cancer by a Novel Proteolysis Targeting Chimera Degrader of Enhancer of Zeste Homolog 2'. Together they form a unique fingerprint.

Cite this