Target Information
| Target General Information | Top | |||||
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| Target ID |
T17986
(Former ID: TTDI03173)
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| Target Name |
Enhancer of zeste homolog 1 (EZH1)
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| Synonyms |
KIAA0388; Histone-lysine N-methyltransferase EZH1; ENX-2
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| Gene Name |
EZH1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 8 Target-related Diseases | + | ||||
| 1 | Mature T-cell lymphoma [ICD-11: 2A90] | |||||
| 2 | Lung cancer [ICD-11: 2C25] | |||||
| 3 | Acute myeloid leukaemia [ICD-11: 2A60] | |||||
| 4 | Malignant haematopoietic neoplasm [ICD-11: 2B33] | |||||
| 5 | Mature B-cell lymphoma [ICD-11: 2A85] | |||||
| 6 | Renal cell carcinoma [ICD-11: 2C90] | |||||
| 7 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| 8 | Ureteral cancer [ICD-11: 2C92] | |||||
| Function |
Catalytic subunit of the PRC2/EED-EZH1 complex, which methylates 'Lys-27' 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. Required for embryonic stem cell derivation and self-renewal, suggesting that it is involved in safeguarding embryonic stem cell identity. Compared to EZH2-containing complexes, it is less abundant in embryonic stem cells, has weak methyltransferase activity and plays a less critical role in forming H3K27me3, which is required for embryonic stem cell identity and proper differentiation. 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 |
MEIPNPPTSKCITYWKRKVKSEYMRLRQLKRLQANMGAKALYVANFAKVQEKTQILNEEW
KKLRVQPVQSMKPVSGHPFLKKCTIESIFPGFASQHMLMRSLNTVALVPIMYSWSPLQQN FMVEDETVLCNIPYMGDEVKEEDETFIEELINNYDGKVHGEEEMIPGSVLISDAVFLELV DALNQYSDEEEEGHNDTSDGKQDDSKEDLPVTRKRKRHAIEGNKKSSKKQFPNDMIFSAI ASMFPENGVPDDMKERYRELTEMSDPNALPPQCTPNIDGPNAKSVQREQSLHSFHTLFCR RCFKYDCFLHPFHATPNVYKRKNKEIKIEPEPCGTDCFLLLEGAKEYAMLHNPRSKCSGR RRRRHHIVSASCSNASASAVAETKEGDSDRDTGNDWASSSSEANSRCQTPTKQKASPAPP QLCVVEAPSEPVEWTGAEESLFRVFHGTYFNNFCSIARLLGTKTCKQVFQFAVKESLILK LPTDELMNPSQKKKRKHRLWAAHCRKIQLKKDNSSTQVYNYQPCDHPDRPCDSTCPCIMT QNFCEKFCQCNPDCQNRFPGCRCKTQCNTKQCPCYLAVRECDPDLCLTCGASEHWDCKVV SCKNCSIQRGLKKHLLLAPSDVAGWGTFIKESVQKNEFISEYCGELISQDEADRRGKVYD KYMSSFLFNLNNDFVVDATRKGNKIRFANHSVNPNCYAKVVMVNGDHRIGIFAKRAIQAG EELFFDYRYSQADALKYVGIERETDVL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | DS-3201b | Drug Info | Phase 2 | T-cell leukaemia | [2] | |
| 2 | DS-3201 | Drug Info | Phase 1 | Acute lymphoblastic leukaemia | [1] | |
| 3 | HH2853 | Drug Info | Phase 1 | Non-hodgkin lymphoma | [3] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 4 Inhibitor drugs | + | ||||
| 1 | DS-3201b | Drug Info | [4] | |||
| 2 | DS-3201 | Drug Info | [1] | |||
| 3 | HH2853 | Drug Info | [5] | |||
| 4 | GSK343 | Drug Info | [6] | |||
| 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: Ademetionine | Ligand Info | |||||
| Structure Description | Structure of human PRC2-EZH1 containing phosphorylated SUZ12 | PDB:7TD5 | ||||
| Method | X-ray diffraction | Resolution | 2.99 Å | Mutation | No | [7] |
| PDB Sequence |
SEYMRLRQLK
30 RLQANMGAKA40 LYVANFAKVQ50 EKTQILNEEW60 KKLRVQPVQS70 MLKKCTIESI 88 FPGFASQHML98 MRSLNTVALV108 PIMYSWSPLQ118 QNFMVEDETV128 LCNIPYMGDE 138 VKEEDETFIE148 ELINNYDGKV158 HGEEQCTPNI277 DGPNAKSVQR287 EQSLHSFHTL 297 FCRRCFKYDC307 FLHPFHATPN317 VYKRKNKEIK327 IEPEPCGTDC337 FLLLEGAKEY 347 AMLHNVEAPS429 PVEWTGAEES440 LFRVFHGTYF450 NNFCSIARLL460 GTKTCKQVFQ 470 FAVKESLILS515 TQVYNYQPCD525 HPDRPCDSTC535 PCIMTQNFCE545 KFCQCNPDCQ 555 NRFPGCRCKT565 QCNTKQCPCY575 LAVRECDPDL585 CLTCGASEHW595 DCKVVSCKNC 605 SIQRGLKKHL615 LLAPSDVAGW625 GTFIKESVQK635 NEFISEYCGE645 LISQDEADRR 655 GKVYDKYMSS665 FLFNLNNDFV675 VDATRKGNKI685 RFANHSVNPN695 CYAKVVMVNG 705 DHRIGIFAKR715 AIQAGEELFF725 DYRYSQADAL735 KYVGIER
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ILE110
4.466
VAL622
3.617
ALA623
2.976
GLY624
3.439
TRP625
2.786
TYR642
4.346
MET663
2.732
SER664
3.592
SER665
3.293
PHE666
3.438
ARG686
3.194
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| Ligand Name: L-serine-O-phosphate | Ligand Info | |||||
| Structure Description | Structure of human PRC2-EZH1 containing phosphorylated SUZ12 | PDB:7TD5 | ||||
| Method | X-ray diffraction | Resolution | 2.99 Å | Mutation | No | [7] |
| PDB Sequence |
SEYMRLRQLK
30 RLQANMGAKA40 LYVANFAKVQ50 EKTQILNEEW60 KKLRVQPVQS70 MLKKCTIESI 88 FPGFASQHML98 MRSLNTVALV108 PIMYSWSPLQ118 QNFMVEDETV128 LCNIPYMGDE 138 VKEEDETFIE148 ELINNYDGKV158 HGEEQCTPNI277 DGPNAKSVQR287 EQSLHSFHTL 297 FCRRCFKYDC307 FLHPFHATPN317 VYKRKNKEIK327 IEPEPCGTDC337 FLLLEGAKEY 347 AMLHNVEAPS429 PVEWTGAEES440 LFRVFHGTYF450 NNFCSIARLL460 GTKTCKQVFQ 470 FAVKESLILS515 TQVYNYQPCD525 HPDRPCDSTC535 PCIMTQNFCE545 KFCQCNPDCQ 555 NRFPGCRCKT565 QCNTKQCPCY575 LAVRECDPDL585 CLTCGASEHW595 DCKVVSCKNC 605 SIQRGLKKHL615 LLAPSDVAGW625 GTFIKESVQK635 NEFISEYCGE645 LISQDEADRR 655 GKVYDKYMSS665 FLFNLNNDFV675 VDATRKGNKI685 RFANHSVNPN695 CYAKVVMVNG 705 DHRIGIFAKR715 AIQAGEELFF725 DYRYSQADAL735 KYVGIER
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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 | 20 | Degree centrality | 2.15E-03 | Betweenness centrality | 1.21E-05 |
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| Closeness centrality | 2.11E-01 | Radiality | 1.37E+01 | Clustering coefficient | 5.89E-01 |
| Neighborhood connectivity | 2.70E+01 | Topological coefficient | 1.67E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| References | Top | |||||
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| REF 1 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 2 | 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 3 | ClinicalTrials.gov (NCT04390737) Evaluate the Safety and Clinical Activity of HH2853. U.S. National Institutes of Health. | |||||
| REF 4 | Development of new agents for peripheral T-cell lymphoma. Expert Opin Biol Ther. 2019 Mar;19(3):197-209. | |||||
| REF 5 | Clinical pipeline report, company report or official report of HaiHe Biopharma. | |||||
| REF 6 | 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 7 | CK2-mediated phosphorylation of SUZ12 promotes PRC2 function by stabilizing enzyme active site. Nat Commun. 2022 Nov 9;13(1):6781. | |||||
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