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

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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, Majer, Christina R, Song, Jeffrey, Scott, Margaret Porter, Jin, Lei, Smith, Jesse J, Olhava, Edward J, Chesworth, Richard, Moyer, Mikel P, Richon, Victoria M, Copeland, Robert A, Keilhack, Heike, Pollock, Roy M, Kuntz, Kevin W·2012·Nature Chemical Biology

DOI 10.1038/nchembio.1084

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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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BindingDB Entry 50013230: Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B-Cell Lymp
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BindingDB (2024) · UC San Diego · doi:10.7270/q2pv6qr8
BindingDB Entry 50016308: Targeting Enhancer of Zeste Homolog 2 for the Treatment of Hematological Malignancies and Solid Tumors: Candidate Structure-Activity Relationships Insights and Evolution Prospects.
BindingDB (2023) · UC San Diego · doi:10.7270/q27d3059
BindingDB Entry 50047724: Identification of novel EZH2 inhibitors through pharmacophore-based virtual screening and biological assays.
BindingDB (2017) · UC San Diego · doi:10.7270/q23n259z
BindingDB Entry 50043403: Small-molecule ligands of methyl-lysine binding proteins: optimization of selectivity for L3MBTL3.
BindingDB (2014) · UC San Diego · doi:10.7270/q2b27wrp
BindingDB Entry 50045685: Selective inhibitors of protein methyltransferases.
BindingDB (2016) · UC San Diego · doi:10.7270/q28k7bs2
BindingDB Entry 50006315: Structure-activity relationship studies of SETD8 inhibitors.
BindingDB (2020) · UC San Diego · doi:10.7270/q2fr00m9
BindingDB Entry 50011730: Design, Synthesis, and Biological Activity of Substrate Competitive SMYD2 Inhibitors.
BindingDB (2022) · UC San Diego · doi:10.7270/q2bg2skf
BindingDB Entry 50046405: Discovery, design, and synthesis of indole-based EZH2 inhibitors.
BindingDB (2016) · UC San Diego · doi:10.7270/q2q24205
BindingDB Entry 50015632: Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2-EED Interaction.
BindingDB (2023) · UC San Diego · doi:10.7270/q27h1phb
BindingDB Entry 50020393: Recent advances in EZH2-based dual inhibitors in the treatment of cancers.
BindingDB (2024) · UC San Diego · doi:10.7270/q2cj8jx9
BindingDB Entry 50009208: Histone methyl transferases: A class of epigenetic opportunities to counter uncontrolled cell proliferation.
BindingDB (2021) · UC San Diego · doi:10.7270/q2pz5d8x
BindingDB Entry 7925: The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex.
BindingDB (2017) · UC San Diego · doi:10.7270/q2ng4pgd

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
ORCID: Knutson, Sarah K
Wigle, Tim J
Klaus, Christine R
Raimondi, Alejandra
Song, Jeffrey
Jin, Lei
Smith, Jesse J
Copeland, Robert A
Pollock, Roy M
Venue: Nature Chemical Biology
Publisher: Springer Science and Business Media LLC
Published: 2012-09-30
Volume: 8
Issue: 11
Pages: 890-896
ISSN: 1552-4450 (ISSN-L)
1552-4469
DOI: 10.1038/nchembio.1084
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
Licence: www.springer.com/tdm (tdm)
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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A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells

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