Target Information
| Target General Information | Top | |||||
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| Target ID |
T25265
(Former ID: TTDI02063)
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| Target Name |
Enhancer of zeste homolog 2 (EZH2)
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| Synonyms |
Lysine Nmethyltransferase 6; Lysine N-methyltransferase 6; KMT6; Histonelysine Nmethyltransferase EZH2; Histone-lysine N-methyltransferase EZH2; EZH2; ENX1; ENX-1
Click to Show/Hide
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| Gene Name |
EZH2
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Follicular lymphoma [ICD-11: 2A80] | |||||
| Function |
Catalytic subunit of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' (H3K9me) and 'Lys-27' (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene. Able to mono-, di- and trimethylate 'Lys-27' of histone H3 to form H3K27me1, H3K27me2 and H3K27me3, respectively. Displays a preference for substrates with less methylation, loses activity when progressively more methyl groups are incorporated into H3K27, H3K27me0 > H3K27me1 > H3K27me2. Compared to EZH1-containing complexes, it is more abundant in embryonic stem cells and plays a major role in forming H3K27me3, which is required for embryonic stem cell identity and proper differentiation. The PRC2/EED-EZH2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems. Genes repressed by the PRC2/EED-EZH2 complex include HOXC8, HOXA9, MYT1, CDKN2A and retinoic acid target genes. EZH2 can also methylate non-histone proteins such as the transcription factor GATA4 and the nuclear receptor RORA. Regulates the circadian clock via histone methylation at the promoter of the circadian genes. Essential for the CRY1/2-mediated repression of the transcriptional activation of PER1/2 by the CLOCK-ARNTL/BMAL1 heterodimer; involved in the di and trimethylation of 'Lys-27' of histone H3 on PER1/2 promoters which is necessary for the CRY1/2 proteins to inhibit transcription. Polycomb group (PcG) protein.
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| BioChemical Class |
Methyltransferase
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| UniProt ID | ||||||
| EC Number |
EC 2.1.1.43
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| Sequence |
MGQTGKKSEKGPVCWRKRVKSEYMRLRQLKRFRRADEVKSMFSSNRQKILERTEILNQEW
KQRRIQPVHILTSVSSLRGTRECSVTSDLDFPTQVIPLKTLNAVASVPIMYSWSPLQQNF MVEDETVLHNIPYMGDEVLDQDGTFIEELIKNYDGKVHGDRECGFINDEIFVELVNALGQ YNDDDDDDDGDDPEEREEKQKDLEDHRDDKESRPPRKFPSDKIFEAISSMFPDKGTAEEL KEKYKELTEQQLPGALPPECTPNIDGPNAKSVQREQSLHSFHTLFCRRCFKYDCFLHPFH ATPNTYKRKNTETALDNKPCGPQCYQHLEGAKEFAAALTAERIKTPPKRPGGRRRGRLPN NSSRPSTPTINVLESKDTDSDREAGTETGGENNDKEEEEKKDETSSSSEANSRCQTPIKM KPNIEPPENVEWSGAEASMFRVLIGTYYDNFCAIARLIGTKTCRQVYEFRVKESSIIAPA PAEDVDTPPRKKKRKHRLWAAHCRKIQLKKDGSSNHVYNYQPCDHPRQPCDSSCPCVIAQ NFCEKFCQCSSECQNRFPGCRCKAQCNTKQCPCYLAVRECDPDLCLTCGAADHWDSKNVS CKNCSIQRGSKKHLLLAPSDVAGWGIFIKDPVQKNEFISEYCGEIISQDEADRRGKVYDK YMCSFLFNLNNDFVVDATRKGNKIRFANHSVNPNCYAKVMMVNGDHRIGIFAKRAIQTGE ELFFDYRYSQADALKYVGIEREMEIP Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T61HJT | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Tazemetostat | Drug Info | Approved | Follicular lymphoma | [2] | |
| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | CPI-1205 | Drug Info | Phase 1/2 | Prostate cancer | [6] | |
| 2 | DS-3201 | Drug Info | Phase 1 | Acute lymphoblastic leukaemia | [6] | |
| 3 | GSK2816126 | Drug Info | Phase 1 | Solid tumour/cancer | [9] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 49 Inhibitor drugs | + | ||||
| 1 | Tazemetostat | Drug Info | [2] | |||
| 2 | CPI-1205 | Drug Info | [6] | |||
| 3 | DS-3201 | Drug Info | [6] | |||
| 4 | PMID26882240-Compound-1 | Drug Info | [11] | |||
| 5 | PMID28394193-Compound-12 | Drug Info | [12] | |||
| 6 | PMID28394193-Compound-13 | Drug Info | [12] | |||
| 7 | PMID28394193-Compound-14 | Drug Info | [12] | |||
| 8 | PMID28394193-Compound-15 | Drug Info | [12] | |||
| 9 | PMID28394193-Compound-16 | Drug Info | [12] | |||
| 10 | PMID28394193-Compound-18 | Drug Info | [12] | |||
| 11 | PMID28394193-Compound-21 | Drug Info | [12] | |||
| 12 | PMID28394193-Compound-22 | Drug Info | [12] | |||
| 13 | PMID28394193-Compound-23 | Drug Info | [12] | |||
| 14 | PMID28394193-Compound-24 | Drug Info | [12] | |||
| 15 | PMID28394193-Compound-25 | Drug Info | [12] | |||
| 16 | PMID28394193-Compound-27 | Drug Info | [12] | |||
| 17 | PMID28394193-Compound-28 | Drug Info | [12] | |||
| 18 | PMID28394193-Compound-29 | Drug Info | [12] | |||
| 19 | PMID28394193-Compound-30 | Drug Info | [12] | |||
| 20 | PMID28394193-Compound-31 | Drug Info | [12] | |||
| 21 | PMID28394193-Compound-32 | Drug Info | [12] | |||
| 22 | PMID28394193-Compound-33 | Drug Info | [12] | |||
| 23 | PMID28394193-Compound-35 | Drug Info | [12] | |||
| 24 | PMID28394193-Compound-36 | Drug Info | [12] | |||
| 25 | PMID28394193-Compound-38 | Drug Info | [12] | |||
| 26 | PMID28394193-Compound-39 | Drug Info | [12] | |||
| 27 | PMID28394193-Compound-40 | Drug Info | [12] | |||
| 28 | PMID28394193-Compound-41 | Drug Info | [12] | |||
| 29 | PMID28394193-Compound-42 | Drug Info | [12] | |||
| 30 | PMID28394193-Compound-43 | Drug Info | [12] | |||
| 31 | PMID28394193-Compound-45 | Drug Info | [12] | |||
| 32 | PMID28394193-Compound-46 | Drug Info | [12] | |||
| 33 | PMID28394193-Compound-47 | Drug Info | [12] | |||
| 34 | PMID28394193-Compound-49 | Drug Info | [12] | |||
| 35 | PMID28394193-Compound-50 | Drug Info | [12] | |||
| 36 | PMID28394193-Compound-51 | Drug Info | [12] | |||
| 37 | PMID28394193-Compound-52 | Drug Info | [12] | |||
| 38 | PMID28394193-Compound-53 | Drug Info | [12] | |||
| 39 | PMID28394193-Compound-54 | Drug Info | [12] | |||
| 40 | PMID28394193-Compound-55 | Drug Info | [12] | |||
| 41 | PMID28394193-Compound-56 | Drug Info | [12] | |||
| 42 | PMID28394193-Compound-57 | Drug Info | [12] | |||
| 43 | PMID28394193-Compound-Figure3bI | Drug Info | [12] | |||
| 44 | PMID28394193-Compound-Figure3bIII | Drug Info | [12] | |||
| 45 | PMID28394193-Compound-Figure5aVIII | Drug Info | [12] | |||
| 46 | EI1 | Drug Info | [13] | |||
| 47 | EPZ005687 | Drug Info | [14] | |||
| 48 | GSK343 | Drug Info | [15] | |||
| 49 | UNC1999 | Drug Info | [16] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | GSK2816126 | Drug Info | [10] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: GSK2816126 | Ligand Info | |||||
| Structure Description | Human Polycomb Repressive Complex 2 in complex with GSK126 inhibitor | PDB:5WG6 | ||||
| Method | X-ray diffraction | Resolution | 3.90 Å | Mutation | No | [17] |
| PDB Sequence |
RFRRADEVKS
40 MFSSNRQKIL50 ERTEILNQEW60 KQRRIQPVHI70 LTSVRECSVT86 SDLDFPTQVI 96 PLKTLNAVAS106 VPIMYSWSPL116 QQNFMVEDTP262 NIDGPNAKSV272 QREQSLHSFH 282 TLFCRRCFKY292 DCFLHPFHAT302 PNTYKRWSGA435 EASMFRVLIG445 TYYDNFCAIA 455 RLIGTKTCRQ465 VYEFRVKVYN519 YQPCDHPRQP529 CDSSCPCVIA539 QNFCEKFCQC 549 SSECQNRFPG559 CRCKAQCNTK569 QCPCYLAVRE579 CDPDLCLTCG589 AADHRDSKNV 599 SCKNCSIQRG609 SKKHLLLAPS619 DVAGWGIFIK629 DPVQKNEFIS639 EYCGEIISQD 649 EADRRGKVYD659 KYMCSFLFNL669 NNDFVVDATR679 KGNKIRFANH689 SVNPNCYAKV 699 MMVNGDHRIG709 IFAKRAIQTG719 EELFFDYRYS729 QNRLYFHSDT2570 CLPLRPQEME 2580 VDSEDEKDPE2590 WLREKTITQI2600 EEFSDVNEGE2610 KEVMKLWNLH2620 VMKHGFIADN 2630 QMNHACMLFV2640 ENYGQKIIKK2650 NLCRNFMLHL2660 VSMHDFNLIS2670 IMSIDKAVTK 2680 LREMQQK
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| Ligand Name: N-Trimethyllysine | Ligand Info | |||||
| Structure Description | Structure of Human Polycomb Repressive Complex 2 (PRC2) with inhibitor | PDB:5LS6 | ||||
| Method | X-ray diffraction | Resolution | 3.47 Å | Mutation | No | [18] |
| PDB Sequence |
KGPVCWRKRV
19 KSEYMRLRQL29 KRFRRADEVK39 SMFSSNRQKI49 LERTEILNQE59 WKQRRIQPVH 69 ILTSVSSLRG79 TRECSVTSDL89 DFPTQVIPLK99 TLNAVASVPI109 MYSWSPLQQN 119 FMVEDETVLH129 NIPYMGDEVL139 DQDGTFIEEL149 IKNYDGKVHG159 DRECGFINDE 169 IFVELVNALG179 QYNESRPPRS220 DKIFEAISSM230 FPDKGTAEEL240 KEKYKELTQP 257 PECTPNIDGP267 NAKSVQREQS277 LHSFHTLFCR287 RCFKYDCFLH297 PFHATPNTYK 307 RKNTETALDN317 KPCGPQCYQH327 LEGAKEFAAA337 LTAERIKTPN423 IEPPENVEWS 433 GAEASMFRVL443 IGTYYDNFCA453 IARLIGTKTC463 RQVYEFRVKE473 SSIIAPAHVY 518 NYQPCDHPRQ528 PCDSSCPCVI538 AQNFCEKFCQ548 CSSECQNRFP558 GCRCKAQCNT 568 KQCPCYLAVR578 ECDPDLCLTC588 GAADHWDSKN598 VSCKNCSIQR608 GSKKHLLLAP 618 SDVAGWGIFI628 KDPVQKNEFI638 SEYCGEIISQ648 DEADRRGKVY658 DKYMCSFLFN 668 LNNDFVVDAT678 RKGNKIRFAN688 HSVNPNCYAK698 VMMVNGDHRI708 GIFAKRAIQT 718 GEELFFDYRY728
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Lysine degradation | hsa00310 | Affiliated Target |
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| Class: Metabolism => Amino acid metabolism | Pathway Hierarchy | ||
| Degree | 55 | Degree centrality | 5.91E-03 | Betweenness centrality | 4.36E-03 |
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| Closeness centrality | 2.61E-01 | Radiality | 1.45E+01 | Clustering coefficient | 1.76E-01 |
| Neighborhood connectivity | 4.35E+01 | Topological coefficient | 4.17E-02 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Drug Resistance Mutation (DRM) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | MicroRNAs in cancer | |||||
| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | IL2 Signaling Pathway | |||||
| Reactome | [+] 3 Reactome Pathways | + | ||||
| 1 | PRC2 methylates histones and DNA | |||||
| 2 | Oxidative Stress Induced Senescence | |||||
| 3 | PKMTs methylate histone lysines | |||||
| WikiPathways | [+] 9 WikiPathways | + | ||||
| 1 | Interactome of polycomb repressive complex 2 (PRC2) | |||||
| 2 | Endoderm Differentiation | |||||
| 3 | Integrated Pancreatic Cancer Pathway | |||||
| 4 | Histone Modifications | |||||
| 5 | Cell Differentiation - meta | |||||
| 6 | miRs in Muscle Cell Differentiation | |||||
| 7 | miR-targeted genes in muscle cell - TarBase | |||||
| 8 | miR-targeted genes in lymphocytes - TarBase | |||||
| 9 | miR-targeted genes in epithelium - TarBase | |||||
| References | Top | |||||
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| REF 1 | Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol Cancer Ther. 2014 Apr;13(4):842-54. | |||||
| REF 2 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020 | |||||
| REF 3 | ClinicalTrials.gov (NCT04102150) Valemetostat Tosylate (DS-3201b) Phase 2 Study in Relapsed or Refractory Adult T-cell Leukemia/Lymphoma. U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT03741712) A Study of SHR2554 Alone or in Combination With SHR3680 in the Treatment of mCRPC. U.S. National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT04104776) A Study of CPI-0209 in Patients With Advanced Tumors. U.S. National Institutes of Health. | |||||
| REF 6 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 7 | ClinicalTrials.gov (NCT03460977) PF-06821497 Treatment Of Relapsed/Refractory SCLC, Castration Resistant Prostate Cancer, and Follicular Lymphoma. U.S. National Institutes of Health. | |||||
| REF 8 | ClinicalTrials.gov (NCT04390737) Evaluate the Safety and Clinical Activity of HH2853. U.S. National Institutes of Health. | |||||
| REF 9 | ClinicalTrials.gov (NCT02082977) A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK2816126 in Subjects With Relapsed/Refractory Diffuse Large B Cell and Transformed Follicular Lymphoma. U.S. National Institutes of Health. | |||||
| REF 10 | National Cancer Institute Drug Dictionary (drug id 756211). | |||||
| REF 11 | Hypoxia-inducible factor (HIF) inhibitors: a patent survey (2011-2015).Expert Opin Ther Pat. 2016;26(3):309-22. | |||||
| REF 12 | EZH2 inhibitors: a patent review (2014-2016).Expert Opin Ther Pat. 2017 Jul;27(7):797-813. | |||||
| REF 13 | Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21360-5. | |||||
| REF 14 | A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol. 2012 Nov;8(11):890-6. | |||||
| REF 15 | Identification of Potent, Selective, Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2. ACS Med Chem Lett. 2012 Oct 19;3(12):1091-6. | |||||
| REF 16 | An orally bioavailable chemical probe of the Lysine Methyltransferases EZH2 and EZH1. ACS Chem Biol. 2013;8(6):1324-34. | |||||
| REF 17 | An Evolutionarily Conserved Structural Platform for PRC2 Inhibition by a Class of Ezh2 Inhibitors. Sci Rep. 2018 Jun 14;8(1):9092. | |||||
| REF 18 | 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. 2016 Nov 10;59(21):9928-9941. | |||||
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