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

Julia Velez1, Brandon Dale1, Kwang-Su Park1

  • 1Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Science, Oncological Science and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

European Journal of Medicinal Chemistry
|January 31, 2024
PubMed

Insights

A novel EZH2 degrader, MS8847, effectively suppresses cancer cell growth by targeting both catalytic and non-catalytic functions of EZH2. This proteolysis-targeting chimera (PROTAC) shows promise in leukemia and breast cancer models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Aberrant EZH2 expression drives various cancers, including leukemia and breast cancer.
  • Non-catalytic functions of EZH2 present therapeutic challenges for traditional inhibitors.
  • Proteolysis-targeting chimeras (PROTACs) offer a novel approach to degrade EZH2.

Purpose of the Study:

  • To introduce MS8847, a potent EZH2 PROTAC degrader utilizing VHL E3 ligase.
  • To evaluate the efficacy of MS8847 against EZH2 in cancer models.
  • To assess MS8847 as a chemical tool for studying EZH2 functions.

Main Methods:

  • Development of MS8847, an EZH2-VHL PROTAC.
  • Assessment of EZH2 degradation in a dose-, time-, and UPS-dependent manner.
  • Evaluation of anti-proliferative effects in MLL-r AML and TNBC cell lines and 3D models.

Main Results:

  • MS8847 demonstrated potent EZH2 degradation and superior anti-proliferative activity in MLL-r AML cells compared to existing PROTACs.
  • MS8847 effectively inhibited cell growth in triple-negative breast cancer (TNBC) cell lines and a 3D model.
  • The compound exhibited favorable pharmacokinetic properties, suggesting in vivo potential.

Conclusions:

  • MS8847 is a highly effective EZH2 PROTAC degrader with significant anti-cancer potential.
  • This novel degrader offers a promising therapeutic strategy for cancers driven by EZH2.
  • MS8847 serves as a valuable tool for further research into EZH2's oncogenic roles.
Keywords:
Acute myeloid leukemiaDegraderEZH2Non-canonical functionPROTACProteolysis-targeting chimeraTriple-negative breast cancer

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