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enhancer of zeste 2 polycomb repressive complex 2 subunit

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2654

Nomenclature: enhancer of zeste 2 polycomb repressive complex 2 subunit

Abbreviated Name: EZH2

Family: 2.1.1.43 Histone methyltransferases (HMTs)

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 746 7q36.1 EZH2 enhancer of zeste 2 polycomb repressive complex 2 subunit
Mouse - 746 6 22.92 cM Ezh2 enhancer of zeste 2 polycomb repressive complex 2 subunit
Rat - 746 4q24 Ezh2 enhancer of zeste 2 polycomb repressive complex 2 subunit
Previous and Unofficial Names Click here for help
enhancer of zeste homolog 2 (Drosophila) | KMT6
Database Links Click here for help
Alphafold Q15910 (Hs), Q61188 (Mm)
ChEMBL Target CHEMBL2189110 (Hs)
Ensembl Gene ENSG00000106462 (Hs), ENSMUSG00000029687 (Mm), ENSRNOG00000006048 (Rn)
Entrez Gene 2146 (Hs), 14056 (Mm), 312299 (Rn)
Human Protein Atlas ENSG00000106462 (Hs)
KEGG Gene hsa:2146 (Hs), mmu:14056 (Mm), rno:312299 (Rn)
OMIM 601573 (Hs)
Pharos Q15910 (Hs)
RefSeq Nucleotide NM_004456 (Hs), NM_007971 (Mm), NM_001134979 (Rn)
RefSeq Protein NP_004447 (Hs), NP_031997 (Mm), NP_001128451 (Rn)
UniProtKB Q15910 (Hs), Q61188 (Mm)
Wikipedia EZH2 (Hs)

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
tulmimetostat Small molecule or natural product Click here for species-specific activity table Hs Inhibition 11.0 pKi 3
⤷ pKi 11.0 (Ki 1.1x10-11 M) [3]
Description: Binding inhibition constant for EZH2
PF-06821497 Small molecule or natural product Ligand has a PDB structure Hs Inhibition >10.0 pKi 13
⤷ pKi >10.0 (Ki <1x10-10 M) [13]
Description: Inhibition of enzyme function in a biochemical assay using the (activating) Y641N mutant form of EZH2.
EPZ011989 Small molecule or natural product Hs Inhibition >8.5 pKi 5
⤷ pKi >8.5 (Ki <3x10-9 M) [5]
EPZ005687 Small molecule or natural product Primary target of this compound Hs Inhibition 7.6 pKi 11
⤷ pKi 7.6 (Ki 2.4x10-8 M) [11]
tulmimetostat Small molecule or natural product Click here for species-specific activity table Hs Inhibition 10.7 pIC50 3
⤷ pIC50 10.7 (IC50 2x10-11 M) [3]
Description: Inhibition of catalytic activity of wild-type EZH2-containing PRC2 complex in a biochemical assay
SKLB-03220 Small molecule or natural product Hs Inhibition 8.8 pIC50 31
⤷ pIC50 8.8 (IC50 1.72x10-9 M) [31]
Description: Inhibition of wild type EZH2 in vitro
UNC1999 Small molecule or natural product Hs Inhibition 8.7 pIC50 12
⤷ pIC50 8.7 (IC50 2x10-9 M) [12]
CPI-1205 Small molecule or natural product Primary target of this compound Hs Inhibition 8.7 pIC50 29
⤷ pIC50 8.7 (IC50 2x10-9 M) [29]
Description: Cell-free biochemical assay
GSK343 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.4 pIC50 30
⤷ pIC50 8.4 (IC50 4x10-9 M) [30]
valemetostat Small molecule or natural product Approved drug Click here for species-specific activity table Hs Inhibition 8.3 pIC50 8
⤷ pIC50 8.3 (IC50 5.1x10-9 M) [8]
EBI-2511 Small molecule or natural product Hs Inhibition 8.1 pIC50 15
⤷ pIC50 8.1 (IC50 8x10-9 M) [15]
Description: Measuring inhibition of EZH2-mediated H3K27 trimethylation in Pfeiffer cells
EI1 Small molecule or natural product Primary target of this compound Hs Inhibition 8.0 pIC50 21
⤷ pIC50 8.0 (IC50 9.4x10-9 M) [21]
GSK126 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 8.0 pIC50 7,19
⤷ pIC50 8.0 (IC50 9.9x10-9 M) [7,19]
Description: Measured using expressed and purified five-member PRC2 protein complex (human Flag–EZH2,EED, SUZ12, AEBP2, RbAp48).
tazemetostat Small molecule or natural product Approved drug Primary target of this compound Hs Inhibition 8.0 pIC50 10
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [10]
JQEZ5 Small molecule or natural product Primary target of this compound Hs Inhibition 8.0 pIC50 26
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [26]
Description: In vitro biochemical assay
compound 15a [PMID: 36642961] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.6 pIC50 27
⤷ pIC50 6.6 (IC50 2.5x10-7 M) [27]
Inhibitor Comments
In vitro GSK126 decreases histone trimethylation (H3K27me3) levels and is able to reactivate silenced PRC2 target genes, and inhibits proliferation of EZH2 mutant diffuse large B-cell lymphoma (DLBCL) cell lines [19]. In vivo GSK126 significantly inhibits the growth of EZH2 mutant DLBCL murine xenografts [19]. EI1 has similar inhibitory function [21]. These findings demonstrate that EZH2 is a druggable target susceptible to pharmacological intervention, with potential benefit in the treatment of EZH2 mutant lymphoma.
EPZ011989 (PubChem CID 73670548) is reported as a potent, orally bioavailable EZH2 inhibitor (Ki <3nM), with significant antiproliferative activity against human B cell lymphoma xenografts [5].
Immunopharmacology Comments
EZH2 is involved in hematopoietic stem cell proliferation and differentiation, thymopoiesis and lymphopoiesis, with notable participation in regulating the differentiation and function of T cells. This role suggests potential applications in immune-mediated conditions, including autoimmune disorders [28] and graft versus host disease (GvHD) [9].
Cell Type Associations
Immuno Cell Type:  T cells
Cell Ontology Term:   CD4-positive helper T cell (CL:0000492)
Comment:  EZH2 has an inhibitory role in the differentiation of Th1 and Th2 cells.
References:  9
Immuno Process Associations
Immuno Process:  Tissue repair
Physiological Functions Click here for help
EZH2 regulates T cell polyfunctional effector cytokine expression and promotes their survival via Bcl-2 signaling.
Species:  Human
Tissue:  T cells
References:  32
EZH2 inhibits T cell Notch repressors.
Species:  Human
Tissue:  T cells
References:  32
Gene silencing: EZH2 is the methyltransferase component of the Polycomb repressive complex PRC2, which catalyzes the trimethylation of histone H3 at Lys27, resulting in epigenetic silencing of target genes.
Species:  Human
Tissue: 
References:  24
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Weaver syndrome
Disease Ontology: DOID:14731
OMIM: 277590
Orphanet: ORPHA3447
General Comments
EZH2 (or EZH1) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) [16] that catalyzes methylation of histone H3 lysine 27 (H3K27) [6,14,16,22]. EZH2 (KMT6) overexpression is implicated in tumorigenesis [1,18,23] and mutations within the catalytic (SET) domain of the enzyme, especially Tyr641 [20], have been identified in large B-cell lymphoma (DLBCL) and follicular lymphoma [4,17,25].

EZH2 inhibitors are being investigated as anti-cancer therapeutics, whereas EZH2 activating agents, driving inhibition of Th1 and Th2 cell differentiation, are suggested as novel interventions for the suppression of Th1- and Th2-dependent autoimmune diseases [9]. In addition, pharmacological inhibition of EZH1 and EZH2 has been shown to induce multiple inflammatory, stress, and antipathogen pathways, and to enhance recruitment of immune cells to virally infected cells in vitro, thereby creating a cellular antiviral state that was suppressive to infection by a range of DNA and RNA viruses [2]. EZH1/2 inhibitors exhibiting this experimental effect were GSK126, GSK343 and UNC1999. This work suggests that EZH1/2 inhibitors can induce a general antiviral defense mechanism.

References

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1. Albert M, Helin K. (2010) Histone methyltransferases in cancer. Semin Cell Dev Biol, 21 (2): 209-20. [PMID:19892027]

2. Arbuckle JH, Gardina PJ, Gordon DN, Hickman HD, Yewdell JW, Pierson TC, Myers TG, Kristie TM. (2017) Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens. MBio, 8 (4). [PMID:28811345]

3. Bradley WD. (2022) Ezh2 inhibition in combination therapies for the treatment of cancers. Patent number: US20220257577A1. Assignee: Constellation Pharmaceuticals Inc. Priority date: 23/07/2020. Publication date: 18/08/2022.

4. Bödör C, Grossmann V, Popov N, Okosun J, O'Riain C, Tan K, Marzec J, Araf S, Wang J, Lee AM et al.. (2013) EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood, 122 (18): 3165-8. [PMID:24052547]

5. Campbell JE, Kuntz KW, Knutson SK, Warholic NM, Keilhack H, Wigle TJ, Raimondi A, Klaus CR, Rioux N, Yokoi A et al.. (2015) EPZ011989, A Potent, Orally-Available EZH2 Inhibitor with Robust in Vivo Activity. ACS Med Chem Lett, 6 (5): 491-5. [PMID:26005520]

6. Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS, Zhang Y. (2002) Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science, 298 (5595): 1039-43. [PMID:12351676]

7. Diaz E, Machutta CA, Chen S, Jiang Y, Nixon C, Hofmann G, Key D, Sweitzer S, Patel M, Wu Z et al.. (2012) Development and validation of reagents and assays for EZH2 peptide and nucleosome high-throughput screens. J Biomol Screen, 17 (10): 1279-92. [PMID:22904200]

8. Honma D, Kanno O, Watanabe J, Kinoshita J, Hirasawa M, Nosaka E, Shiroishi M, Takizawa T, Yasumatsu I, Horiuchi T et al.. (2017) Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor. Cancer Sci, 108 (10): 2069-2078. [PMID:28741798]

9. Karantanos T, Chistofides A, Barhdan K, Li L, Boussiotis VA. (2016) Regulation of T Cell Differentiation and Function by EZH2. Front Immunol, 7: 172. [PMID:27199994]

10. Knutson SK, Warholic NM, Wigle TJ, Klaus CR, Allain CJ, Raimondi A, Porter Scott M, Chesworth R, Moyer MP, Copeland RA et al.. (2013) Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci USA, 110 (19): 7922-7. [PMID:23620515]

11. Knutson SK, Wigle TJ, Warholic NM, Sneeringer CJ, Allain CJ, Klaus CR, Sacks JD, Raimondi A, Majer CR, Song J et al.. (2012) A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol, 8 (11): 890-6. [PMID:23023262]

12. Konze KD, Ma A, Li F, Barsyte-Lovejoy D, Parton T, Macnevin CJ, Liu F, Gao C, Huang XP, Kuznetsova E et al.. (2013) An orally bioavailable chemical probe of the Lysine Methyltransferases EZH2 and EZH1. ACS Chem Biol, 8 (6): 1324-34. [PMID:23614352]

13. Kung PP, Bingham P, Brooun A, Collins M, Deng YL, Dinh D, Fan C, Gajiwala KS, Grantner R, Gukasyan HJ et al.. (2018) Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497). J Med Chem, 61 (3): 650-665. [PMID:29211475]

14. Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D. (2002) Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev, 16 (22): 2893-905. [PMID:12435631]

15. Lu B, Shen X, Zhang L, Liu D, Zhang C, Cao J, Shen R, Zhang J, Wang D, Wan H et al.. (2018) Discovery of EBI-2511: A Highly Potent and Orally Active EZH2 Inhibitor for the Treatment of Non-Hodgkin's Lymphoma. ACS Med Chem Lett, 9 (2): 98-102. [PMID:29456795]

16. Margueron R, Li G, Sarma K, Blais A, Zavadil J, Woodcock CL, Dynlacht BD, Reinberg D. (2008) Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. Mol Cell, 32 (4): 503-18. [PMID:19026781]

17. Margueron R, Reinberg D. (2011) The Polycomb complex PRC2 and its mark in life. Nature, 469 (7330): 343-9. [PMID:21248841]

18. Martin C, Zhang Y. (2005) The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol, 6 (11): 838-49. [PMID:16261189]

19. McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, Liu Y, Graves AP, Della Pietra 3rd A, Diaz E et al.. (2012) EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature, 492 (7427): 108-12. [PMID:23051747]

20. Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, Paul JE, Boyle M, Woolcock BW, Kuchenbauer F et al.. (2010) Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet, 42 (2): 181-5. [PMID:20081860]

21. Qi W, Chan H, Teng L, Li L, Chuai S, Zhang R, Zeng J, Li M, Fan H, Lin Y et al.. (2012) Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc Natl Acad Sci USA, 109 (52): 21360-5. [PMID:23236167]

22. Shen X, Liu Y, Hsu YJ, Fujiwara Y, Kim J, Mao X, Yuan GC, Orkin SH. (2008) EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. Mol Cell, 32 (4): 491-502. [PMID:19026780]

23. Shiogama S, Yoshiba S, Soga D, Motohashi H, Shintani S. (2013) Aberrant expression of EZH2 is associated with pathological findings and P53 alteration. Anticancer Res, 33 (10): 4309-17. [PMID:24122997]

24. Simon JA, Kingston RE. (2009) Mechanisms of polycomb gene silencing: knowns and unknowns. Nat Rev Mol Cell Biol, 10 (10): 697-708. [PMID:19738629]

25. Sneeringer CJ, Scott MP, Kuntz KW, Knutson SK, Pollock RM, Richon VM, Copeland RA. (2010) Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc Natl Acad Sci USA, 107 (49): 20980-5. [PMID:21078963]

26. Souroullas GP, Jeck WR, Parker JS, Simon JM, Liu JY, Paulk J, Xiong J, Clark KS, Fedoriw Y, Qi J et al.. (2016) An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation. Nat Med, 22 (6): 632-40. [PMID:27135738]

27. Tang H, Yu A, Xing L, Chen X, Ding H, Yang H, Song Z, Shi Q, Geng M, Huang X et al.. (2023) Structural Modification and Pharmacological Evaluation of Substituted Quinoline-5,8-diones as Potent NSD2 Inhibitors. J Med Chem, 66 (2): 1634-1651. [PMID:36642961]

28. Tsou PS, Coit P, Kilian NC, Sawalha AH. (2018) EZH2 Modulates the DNA Methylome and Controls T Cell Adhesion Through Junctional Adhesion Molecule A in Lupus Patients. Arthritis Rheumatol, 70 (1): 98-108. [PMID:28973837]

29. Vaswani RG, Gehling VS, Dakin LA, Cook AS, Nasveschuk CG, Duplessis M, Iyer P, Balasubramanian S, Zhao F, Good AC et al.. (2016) 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 Lymphomas. J Med Chem, 59 (21): 9928-9941. [PMID:27739677]

30. Verma SK, Tian X, LaFrance LV, Duquenne C, Suarez DP, Newlander KA, Romeril SP, Burgess JL, Grant SW, Brackley JA et al.. (2012) Identification of Potent, Selective, Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2. ACS Med Chem Lett, 3 (12): 1091-6. [PMID:24900432]

31. Zhang Q, Chen X, Cao J, Yang W, Wan G, Feng Q, Zhou S, Yang H, Wang N, Liu Z et al.. (2023) Discovery of a Novel Covalent EZH2 Inhibitor Based on Tazemetostat Scaffold for the Treatment of Ovarian Cancer. J Med Chem, 66 (3): 1725-1741. [PMID:36692394]

32. Zhao E, Maj T, Kryczek I, Li W, Wu K, Zhao L, Wei S, Crespo J, Wan S, Vatan L et al.. (2016) Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat Immunol, 17 (1): 95-103. [PMID:26523864]

How to cite this page

2.1.1.43 Histone methyltransferases (HMTs): enhancer of zeste 2 polycomb repressive complex 2 subunit. Last modified on 19/04/2023. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2654.