Discovery of a novel, highly potent EZH2 PROTAC degrader for targeting non-canonical oncogenic functions of EZH2

Julia Velez, Brandon Dale, Kwang Su Park, H. Ümit Kaniskan, Xufen Yu, Jian Jin

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Aberrant expression of EZH2, the main catalytic subunit of PRC2, has been implicated in numerous cancers, including leukemia, breast, and prostate. Recent studies have highlighted non-catalytic oncogenic functions of EZH2, which EZH2 catalytic inhibitors cannot attenuate. Therefore, proteolysis-targeting chimera (PROTAC) degraders have been explored as an alternative therapeutic approach to suppress both canonical and non-canonical oncogenic activity. Here we present MS8847, a novel, highly potent EZH2 PROTAC degrader that recruits the E3 ligase von Hippel-Lindau (VHL). MS8847 degrades EZH2 in a concentration-, time-, and ubiquitin–proteasome system (UPS)-dependent manner. Notably, MS8847 induces superior EZH2 degradation and anti-proliferative effects in MLL-rearranged (MLL-r) acute myeloid leukemia (AML) cells compared to previously published EZH2 PROTAC degraders. Moreover, MS8847 degrades EZH2 and inhibits cell growth in triple-negative breast cancer (TNBC) cell lines, displays efficacy in a 3D TNBC in vitro model, and has a pharmacokinetic (PK) profile suitable for in vivo efficacy studies. Overall, MS8847 is a valuable chemical tool for the biomedical community to investigate canonical and non-canonical oncogenic functions of EZH2.

Original languageEnglish
Article number116154
JournalEuropean Journal of Medicinal Chemistry
Volume267
DOIs
StatePublished - 5 Mar 2024

Keywords

  • Acute myeloid leukemia
  • Degrader
  • EZH2
  • Non-canonical function
  • PROTAC
  • Proteolysis-targeting chimera
  • Triple-negative breast cancer

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