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A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells
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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“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 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [173]
Citations
Cites
Improved survival with vemurafenib in melanoma with BRAF V600E mutation
Chapman, P. B., Hauschild, A., Robert, C., Haanen, J. B., Ascierto, P., Larkin, J., Dummer, R., Garbe, C., Testori, A., Maio, M., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1103782 · Cited by 7,720
Anaplastic Lymphoma Kinase Inhibition in Non–Small-Cell Lung Cancer
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
The polycomb group protein EZH2 is involved in progression of prostate cancer
Varambally, S., Dhanasekaran, S. M., Zhou, M., Barrette, T. R., Kumar-Sinha, C., Sanda, M. G., Ghosh, D., Pienta, K. J., Sewalt, R. G. A. B., Otte, A. P., et al. (2002) · Nature · doi:10.1038/nature01075 · Cited by 2,717
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
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
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
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
Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity
Tsai, J., Lee, J. T., Wang, W., Zhang, J., Cho, H., Mamo, S., Bremer, R., Gillette, S., Kong, J., Haass, N. K., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0711741105 · Cited by 1,346
Role of the polycomb protein EED in the propagation of repressive histone marks
Margueron, R., Justin, N., Ohno, K., Sharpe, M. L., Son, J., Drury, W. J., Voigt, P., Martin, S. R., Taylor, W. R., Marco, V. D., et al. (2009) · Nature · doi:10.1038/nature08398 · Cited by 1,281
EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer.
Bracken, A. P., Pasini, D., Capra, M., Prosperini, E., Colli, E., & Helin, K. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg542 · Cited by 1,196
Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders
Ernst, T., Chase, A. J., Score, J., Hidalgo-Curtis, C. E., Bryant, C., Jones, A. V., Waghorn, K., Zoi, K., Ross, F. M., Reiter, A., et al. (2010) · Nature Genetics · doi:10.1038/ng.621 · Cited by 1,139
Copeland, R. A. (2005) · PubMed · Cited by 1,045
Self-citationLohr, J. G., Stojanov, P., Lawrence, M. S., Auclair, D., Chapuy, B., Sougnez, C. L., Cruz‐Gordillo, P., Knoechel, B., Asmann, Y. W., Slager, S. L., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1121343109 · Cited by 992
De Santa, F., Totaro, M. G., Prosperini, E., Notarbartolo, S., Testa, G., & Natoli, G. (2007) · Cell · doi:10.1016/j.cell.2007.08.019 · Cited by 965
Selective Killing of Mixed Lineage Leukemia Cells by a Potent Small-Molecule DOT1L Inhibitor
Daigle, S. R., Olhava, E. J., Therkelsen, C. A., Majer, C. R., Sneeringer, C. J., Song, J. J., Johnston, L. D., Scott, M. P., Smith, J. J., Xiao, Y., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.06.009 · Cited by 926
Self-citationTan, J., Yang, X., Zhuang, L., Jiang, X., Chen, W., Lee, P. L., Karuturi, R. K. M., Tan, P. B. O., Liu, E. T., & Yu, Q. (2007) · Genes & Development · doi:10.1101/gad.1524107 · Cited by 895
Roles of the EZH2 histone methyltransferase in cancer epigenetics
Simon, J. A., & Lange, C. A. (2008) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2008.07.010 · Cited by 880
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Lan, F., Bayliss, P. E., Rinn, J. L., Whetstine, J. R., Wang, J. K., Chen, S., Iwase, S., Alpatov, R., Issaeva, I., Canaani, E., et al. (2007) · Nature · doi:10.1038/nature06192 · Cited by 808
Demethylation of H3K27 Regulates Polycomb Recruitment and H2A Ubiquitination
Lee, M. G., Villa, R., Trojer, P., Norman, J. A., Yan, K.-P., Reinberg, D., Croce, L. D., & Shiekhattar, R. (2007) · Science · doi:10.1126/science.1149042 · Cited by 789
Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer
van Haaften, G., Dalgliesh, G. L., Davies, H., Chen, L., Bignell, G., Greenman, C., Edkins, S., Hardy, C., O'Meara, S., Teague, J., et al. (2009) · Nature Genetics · doi:10.1038/ng.349 · Cited by 784
Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes
Nikoloski, G., Langemeijer, S. M. C., Kuiper, R. P., Knops, R., Massop, M., Tönnissen, E., van der Heijden, A., Scheele, T. N., Vandenberghe, P., de Witte, T., et al. (2010) · Nature Genetics · doi:10.1038/ng.620 · Cited by 777
Sneeringer, C. J., Scott, M. P., Kuntz, K. W., Knutson, S. K., Pollock, R. M., Richon, V. M., & Copeland, R. A. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1012525107 · Cited by 719
Self-citationIdentification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases
Hong, S., Cho, Y., Yu, L., Yu, H., Veenstra, T. D., & Ge, K. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0707292104 · Cited by 716
Evaluation of Enzyme Inhibitors in Drug Discovery
Copeland, R. A. (2013) · Wiley eBooks · doi:10.1002/9781118540398 · Cited by 689
Self-citationYap, D., Chu, J., Berg, T., Schapira, M., Cheng, S., Moradian, A., Morin, R. D., Mungall, A. J. J., Meissner, B., Boyle, M., et al. (2010) · Blood · doi:10.1182/blood-2010-11-321208 · Cited by 633
Miranda, T. B., Cortez, C. C., Yoo, C. B., Liang, G., Abe, M., Kelly, T. K., Márquez, V. E., & Jones, P. A. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-0013 · Cited by 609
Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia
Ntziachristos, P., Tsirigos, A., Vlierberghe, P. V., Nedjic, J., Trimarchi, T., Flaherty, M. S., Ferrés-Marcó, D., Ros, V. G. D., Tang, Z., Siegle, J., et al. (2012) · Nature Medicine · doi:10.1038/nm.2651 · Cited by 548
A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells
Vedadi, M., Baršytė-Lovejoy, D., Liu, F., Rival‐Gervier, S., Allali‐Hassani, A., Labrie, V., Wigle, T. J., DiMaggio, P. A., Wasney, G. A., Siarheyeva, A., et al. (2011) · Nature Chemical Biology · doi:10.1038/nchembio.599 · Cited by 547
Self-citationMcCabe, M. T., Graves, A. P., Ganji, G., Diaz, E., Halsey, W. S., Jiang, Y., Smitheman, K. N., Ott, H. M., Pappalardi, M. B., Allen, K. E., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1116418109 · Cited by 511
Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27Preprint
Kirmizis, A., Bartley, S. M., Kuzmichev, A., Margueron, R., Reinberg, D., Green, R., & Farnham, P. (2004) · Genes & Development · doi:10.1101/gad.1200204 · Cited by 503
Protein methyltransferases as a target class for drug discovery
Copeland, R. A., Solomon, M. E., & Richon, V. M. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2974 · Cited by 480
Self-citationHow many mutations are required for tumorigenesis? implications from human cancer data
Balmain, A., Barrett, J. C., Moses, H. L., & Renan, M. J. (1993) · Molecular Carcinogenesis · doi:10.1002/mc.2940070303 · Cited by 463
Velichutina, I., Shaknovich, R., Geng, H., Johnson, N. A., Gascoyne, R. D., Melnick, A. M., & Elemento, O. (2010) · Blood · doi:10.1182/blood-2010-04-280149 · Cited by 319
Studies on liver alcohol dehydrogenase complexes
Yonetani, T., & Theorell, H. (1964) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(64)90184-5 · Cited by 281
Dornan, D., Bennett, F. L., Chen, Y., Dennis, M. S., Eaton, D., Elkins, K., French, D. M., Go, M. A. T., Jack, A., Junutula, J. R., et al. (2009) · Blood · doi:10.1182/blood-2009-02-205500 · Cited by 273
Xu, C., Bian, C., Yang, W., Galka, M., Ouyang, H., Chen, C., Qiu, W., Liu, H., Jones, A. E., MacKenzie, F., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1008937107 · Cited by 232
Chemogenetic Analysis of Human Protein Methyltransferases
Richon, V. M., Johnston, D., Sneeringer, C. J., Jin, L., Majer, C. R., Elliston, K. O., Jerva, L. F., Scott, M. P., & Copeland, R. A. (2011) · Chemical Biology & Drug Design · doi:10.1111/j.1747-0285.2011.01135.x · Cited by 195
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Han, Z., Xing, X., Hu, M., Zhang, Y., Liu, P., & Chai, J. (2007) · Structure · doi:10.1016/j.str.2007.08.007 · Cited by 161
A novel human homologue of Drosophila polycomblike gene is up-regulated in multiple cancers
Wang, S., Robertson, G. P., & Zhu, J. (2004) · Gene · doi:10.1016/j.gene.2004.09.006 · Cited by 98
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Wigle, T. J., Knutson, S. K., Jin, L., Kuntz, K. W., Pollock, R. M., Richon, V. M., Copeland, R. A., & Scott, M. P. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.08.018 · Cited by 94
Self-citationChoosing anticancer drug targets in the postgenomic era
Kaelin, W. G. (1999) · Journal of Clinical Investigation · doi:10.1172/jci8888 · Cited by 79
(2009) · Wiley eBooks · doi:10.1002/9780470524961 · Cited by 60
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Metadata
- 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
- 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
- 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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