Cited by 807Epigenetics and DNA MethylationCancer-related gene regulationChromatin Remodeling and Cancer

A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells

Knutson, Sarah K, Wigle, Tim J, Warholic, Natalie M, Sneeringer, Christopher J, Allain, Christina J, Klaus, Christine R, Sacks, Joelle D, Raimondi, Alejandra +13 more·2012·Nature Chemical Biology

Abstract

EZH2 catalyzes trimethylation of histone H3 lysine 27 (H3K27). Point mutations of EZH2 at Tyr641 and Ala677 occur in subpopulations of non-Hodgkin's lymphoma, where they drive H3K27 hypertrimethylation. Here we report the discovery of EPZ005687, a potent inhibitor of EZH2 (K(i) of 24 nM). EPZ005687 has greater than 500-fold selectivity against 15 other protein methyltransferases and has 50-fold selectivity against the closely related enzyme EZH1. The compound reduces H3K27 methylation in various lymphoma cells; this translates into apoptotic cell killing in heterozygous Tyr641 or Ala677 mutant cells, with minimal effects on the proliferation of wild-type cells. These data suggest that genetic alteration of EZH2 (for example, mutations at Tyr641 or Ala677) results in a critical dependency on enzymatic activity for proliferation (that is, the equivalent of oncogene addiction), thus portending the clinical use of EZH2 inhibitors for cancers in which EZH2 is genetically altered.

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Crossref · 10.1038/nchembio.1084

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  • PRMT5 has been implicated in driving neoplastic growth of multiple tumours including B cell lymphoma, multiple myeloma, breast cancer and glioblastoma.

    “More recently, the arginine methyltransferase PRMT5 has been implicated in driving neoplastic growth of multiple tumours including B cell lymphoma, multiple myeloma, breast cancer and glioblastoma 171-178 .”

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Authors
Knutson, S. K., Wigle, T. J., Warholic, N. M., Sneeringer, C. J., Allain, C. J., Klaus, C. R., Sacks, J. D., Raimondi, A., Majer, C. R., Song, J., Scott, M. P., Jin, L., Smith, J. J., Olhava, E. J., Chesworth, R., Moyer, M. P., Richon, V. M., Copeland, R. A., Keilhack, H., Pollock, R. M., & Kuntz, K. W.
Affiliations
Epizyme (United States) (US)
Corresponding author
Kuntz, Kevin W
Venue
Nature Chemical Biology
Published
2012-09-30
Volume
8
Issue
11
Pages
890-896
ISSN
  • 1552-4450 (ISSN-L)
  • 1552-4469
OpenAlex
W2017492512
Cited by
776
References
46
Citations by year
2026: 20 · 2025: 29 · 2024: 29 · 2023: 39 · 2022: 38 · 2021: 49 · 2020: 42 · 2019: 44 · 2018: 60 · 2017: 83 · 2016: 78 · 2015: 97 · 2014: 89 · 2013: 69 · 2012: 10
FWCI
34.74
Type
journal article
Language
en
Open access
closed
Locations
  • Nature Chemical Biology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
EZH2, H3K27me3, polycomb repressive complex 2, EZH2 inhibitors, non-Hodgkin lymphoma, oncogene addiction, apoptosis, histone methyltransferase inhibitors
MeSH terms
Enhancer of Zeste Homolog 2 Protein, Antineoplastic Agents, Cell Cycle, Dose-Response Relationship, Drug, Enzyme Inhibitors, Histones, Humans, Indazoles, Lymphoma, Lysine, Methylation, Pyridones, Structure-Activity Relationship, Molecular Structure, Cell Death, Point Mutation, Cell Proliferation, Polycomb Repressive Complex 2

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