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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Kwak, E. L., Bang, Y., Camidge, D. R., Shaw, A. T., Solomon, B., Maki, R. G., Ou, S. I., Dezube, B. J., Janne, P. A., Costa, D. B., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1006448 · Cited by 4,477
Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing
Cao, R., Wang, L., Wang, H., Xia, L., Erdjument-Bromage, H., Tempst, P., Jones, R. S., & Zhang, Y. (2002) · Science · doi:10.1126/science.1076997 · Cited by 3,775
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An embryonic stem cell–like gene expression signature in poorly differentiated aggressive human tumors
Ben‐Porath, I., Thomson, M., Carey, V. J., Ge, R., Bell, G. W., Regev, A., & Weinberg, R. A. (2008) · Nature Genetics · doi:10.1038/ng.127 · Cited by 2,571
Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin
Morin, R. D., Johnson, N. A., Severson, T., Mungall, A. J. J., An, J., Goya, R., Paul, J. E., Boyle, M., Woolcock, B. W., Kuchenbauer, F. C., et al. (2010) · Nature Genetics · doi:10.1038/ng.518 · Cited by 1,719
EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells
Kleer, C. G., Cao, Q., Varambally, S., Shen, R., Ota, I., Tomlins, S. A., Ghosh, D., Sewalt, R. G. A. B., Otte, A. P., Hayes, D. F., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1933744100 · Cited by 1,649
Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma
Morin, R. D., Mendez-Lago, M., Mungall, A. J., Goya, R., Mungall, K. L., Corbett, R. D., Johnson, N. A., Severson, T. M., Chiu, R., Field, M., et al. (2011) · Nature · doi:10.1038/nature10351 · Cited by 1,614
Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein
Kuzmichev, A., Nishioka, K., Erdjument-Bromage, H., Tempst, P., & Reinberg, D. (2002) · Genes & Development · doi:10.1101/gad.1035902 · Cited by 1,596
UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development
Agger, K., Cloos, P. A., Christensen, J. F., Pasini, D., Rose, S., Rappsilber, J., Issaeva, I., Canaani, E., Salcini, A. E., & Helin, K. (2007) · Nature · doi:10.1038/nature06145 · Cited by 1,392

Show all 46 references

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Alzrigat, M., Párraga, A. A., & Jernberg‐Wiklund, H. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.09.007 · Cited by 95
Polycomb proteins control proliferation and transformation independently of cell cycle checkpoints by regulating DNA replication
Piunti, A., Rossi, A., Cerutti, A., Albert, M., Jammula, S., Scelfo, A., Cedrone, L., Fragola, G., Olsson, L., Koseki, H., et al. (2014) · Nature Communications · doi:10.1038/ncomms4649 · Cited by 93
Oncogenic Y641 mutations in EZH2 prevent Jak2/β-TrCP-mediated degradation
Sahasrabuddhe, A. A., Chen, X., Feng, F. Y.-C., Velusamy, T., Lim, M. S., & Elenitoba‐Johnson, K. S. J. (2014) · Oncogene · doi:10.1038/onc.2013.571 · Cited by 98
Emerging concepts of epigenetic dysregulation in hematological malignancies
Ntziachristos, P., Abdel-Wahab, O. I., & Aifantis, I. (2016) · Nature Immunology · doi:10.1038/ni.3517 · Cited by 99
A chemical probe toolbox for dissecting the cancer epigenome
Shortt, J., Ott, C. J., Johnstone, R. W., & Bradner, J. E. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2016.148 · Cited by 94
Epigenetic Enzyme Mutations: Role in Tumorigenesis and Molecular Inhibitors
Han, M., Jia, L., Lv, W., Wang, L., & Cui, W. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00194 · Cited by 99
Epigenetic regulators in cancer therapy and progression
Marei, H. E. S. (2025) · npj Precision Oncology · doi:10.1038/s41698-025-01003-7 · Cited by 116
The inhibition of EZH2 ameliorates osteoarthritis development through the Wnt/β-catenin pathway
Chen, L., Wu, Y., Wu, Y. R., Wang, Y., Sun, L., & Li, F. (2016) · Scientific Reports · doi:10.1038/srep29176 · Cited by 95
Role of EZH2 in cancer stem cells: from biological insight to a therapeutic target
Wen, Y., Cai, J., Hou, Y., Huang, Z., & Wang, Z. (2017) · Oncotarget · doi:10.18632/oncotarget.16467 · Cited by 91
EZH2 as a potential target in cancer therapy
McCabe, M. T., & Creasy, C. L. (2014) · Epigenomics · doi:10.2217/epi.14.23 · Cited by 91
Epigenetics in Cancer: A Hematological Perspective
Stahl, M. F., Kohrman, N., Gore, S. D., Kim, T. K., Zeidan, A. M., & Prébet, T. (2016) · PLoS Genetics · doi:10.1371/journal.pgen.1006193 · Cited by 92
Precision therapy for lymphoma—current state and future directions
Intlekofer, A. M., & Younes, A. (2014) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2014.137 · Cited by 91
Epigenetic modulators as therapeutic targets in prostate cancer
Graça, I. C. R., Pereira-Silva, E., Henrique, R., Packham, G., Crabb, S. J., & Jerónimo, C. (2016) · Clinical Epigenetics · doi:10.1186/s13148-016-0264-8 · Cited by 90
Inhibition of LSD1 reduces herpesvirus infection, shedding, and recurrence by promoting epigenetic suppression of viral genomes
Hill, J. M., Quenelle, D. C., Cardin, R. D., Vogel, J. L., Clément, C., Bravo, F., Foster, T. P., Bosch‐Marcé, M., Raja, P., Lee, J. S., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3010643 · Cited by 87
Molecular Pathways: Metabolic Control of Histone Methylation and Gene Expression in Cancer
Tran, T. Q., Lowman, X. H., & Kong, M. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-2506 · Cited by 91
Illuminating the noncoding genome in cancer
Zhang, X., & Meyerson, M. M. (2020) · Nature Cancer · doi:10.1038/s43018-020-00114-3 · Cited by 86
Orthogonal Regulation of Nucleophilic and Electrophilic Sites in Pd‐Catalyzed Regiodivergent Couplings between Indazoles and Isoprene
Jiang, W., Ji, D., Zhang, W., Zhang, G., Min, X., Hu, Y., Jiang, X., & Chen, Q. (2021) · Angewandte Chemie International Edition · doi:10.1002/anie.202100137 · Cited by 88
EZH2 Promotes E2F-Driven SCLC Tumorigenesis through Modulation of Apoptosis and Cell-Cycle Regulation
Hubaux, R., Thu, K. L., Coe, B. P., MacAulay, C. E., Lam, S. C., & Lam, W. L. (2013) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e318298762f · Cited by 88
Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells
Curry, E. W., Green, I., Chapman‐Rothe, N., Shamsaei, E., Kandil, S., Cherblanc, F., Payne, L., Bell, E., Ganesh, T., Srimongkolpithak, N., et al. (2015) · Clinical Epigenetics · doi:10.1186/s13148-015-0118-9 · Cited by 91
Genetic lesions in diffuse large B-cell lymphomas
Testoni, M., Zucca, E., Young, K. H., & Bertoni, F. (2015) · Annals of Oncology · doi:10.1093/annonc/mdv019 · Cited by 89
Digging deep into “dirty” drugs – modulation of the methylation machinery
Pleyer, L., & Greil, R. (2015) · Drug Metabolism Reviews · doi:10.3109/03602532.2014.995379 · Cited by 84
“Several small molecule inhibitors of EZH2 have been developed, and shown to induce tumor regression in hematologic tumor models (Knutson et al., 2012; McCabe et al., 2012; Qi et al., 2012).”
Background
Multifaceted role of EZH2 in breast and prostate tumorigenesis
Deb, G., Thakur, V. S., & Gupta, S. (2013) · Epigenetics · doi:10.4161/epi.24532 · Cited by 92
In Vivo Disruption of an Rb–E2F–Ezh2 Signaling Loop Causes Bladder Cancer
Santos, M., Martínez‐Fernández, M., Dueñas, M., García‐Escudero, R., Alfaya, B., Villacampa, F., Sáiz-Ladera, C., Costa, C., Oteo, M., Duarte, J. M., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-1218 · Cited by 84
Weaver Syndrome‐Associated EZH2 Protein Variants Show Impaired Histone Methyltransferase Function In Vitro
Cohen, A. S. A., Yap, D., Lewis, M. E. S., Chijiwa, C., Ramos‐Arroyo, M. A., Tkachenko, N., Milano, V., Fradin, M., McKinnon, M. L., Townsend, K. N., et al. (2015) · Human Mutation · doi:10.1002/humu.22946 · Cited by 92
Protein Methyltransferases: A Distinct, Diverse, and Dynamic Family of Enzymes
Boriack‐Sjodin, P. A., & Swinger, K. K. (2015) · Biochemistry · doi:10.1021/acs.biochem.5b01129 · Cited by 84
Targeting histone methyltransferase EZH2 as cancer treatment
Kondo, Y. (2014) · The Journal of Biochemistry · doi:10.1093/jb/mvu054 · Cited by 82
A Chemical Genetics Approach for the Functional Assessment of Novel Cancer Genes
Zhou, Q., Derti, A., Ruddy, D. A., Rakiec, D. P., Kao, I., Lira, M., Gibaja, V., Chan, H., Yang, Y., Min, J., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-2930 · Cited by 85
Targeting epigenetic regulators for cancer therapy
Wee, S., Dhanak, D., Li, H., Armstrong, S. A., Copeland, R. A., Sims, R. J., Baylin, S. B., Liu, X. S., & Schweizer, L. (2014) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12356 · Cited by 81
Self-citation
The Roles of Post-Translational Modifications in STAT3 Biological Activities and Functions
Tesoriere, A., Dinarello, A., & Argenton, F. (2021) · Biomedicines · doi:10.3390/biomedicines9080956 · Cited by 80
A transgenic mouse model demonstrating the oncogenic role of mutations in the polycomb-group gene EZH2 in lymphomagenesis
Berg, T., Thoene, S., Yap, D., Wee, T., Schoeler, N., Rosten, P., Lim, E. L., Bilenky, M., Mungall, A. J. J., Oellerich, T., et al. (2014) · Blood · doi:10.1182/blood-2012-12-473439 · Cited by 87
CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis
Greenblatt, S. M., Man, N., Hamard, P.-J., Asai, T., Karl, D. L., Martínez, C., Bilbao, D., Stathias, V., Jermakowicz, A. M., Duffort, S., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.05.007 · Cited by 80

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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