Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT9MZCQ)

DTT Name Enhancer of zeste homolog 2 (EZH2)
Synonyms Lysine Nmethyltransferase 6; Lysine N-methyltransferase 6; KMT6; Histonelysine Nmethyltransferase EZH2; Histone-lysine N-methyltransferase EZH2; EZH2; ENX1; ENX-1
Gene Name EZH2
DTT Type
Successful target
 [1]
BioChemical Class
Methyltransferase
UniProt ID
EZH2_HUMAN
TTD ID
T25265
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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EC Number
EC 2.1.1.43
Sequence
MGQTGKKSEKGPVCWRKRVKSEYMRLRQLKRFRRADEVKSMFSSNRQKILERTEILNQEW
KQRRIQPVHILTSVSSLRGTRECSVTSDLDFPTQVIPLKTLNAVASVPIMYSWSPLQQNF
MVEDETVLHNIPYMGDEVLDQDGTFIEELIKNYDGKVHGDRECGFINDEIFVELVNALGQ
YNDDDDDDDGDDPEEREEKQKDLEDHRDDKESRPPRKFPSDKIFEAISSMFPDKGTAEEL
KEKYKELTEQQLPGALPPECTPNIDGPNAKSVQREQSLHSFHTLFCRRCFKYDCFLHPFH
ATPNTYKRKNTETALDNKPCGPQCYQHLEGAKEFAAALTAERIKTPPKRPGGRRRGRLPN
NSSRPSTPTINVLESKDTDSDREAGTETGGENNDKEEEEKKDETSSSSEANSRCQTPIKM
KPNIEPPENVEWSGAEASMFRVLIGTYYDNFCAIARLIGTKTCRQVYEFRVKESSIIAPA
PAEDVDTPPRKKKRKHRLWAAHCRKIQLKKDGSSNHVYNYQPCDHPRQPCDSSCPCVIAQ
NFCEKFCQCSSECQNRFPGCRCKAQCNTKQCPCYLAVRECDPDLCLTCGAADHWDSKNVS
CKNCSIQRGSKKHLLLAPSDVAGWGIFIKDPVQKNEFISEYCGEIISQDEADRRGKVYDK
YMCSFLFNLNNDFVVDATRKGNKIRFANHSVNPNCYAKVMMVNGDHRIGIFAKRAIQTGE
ELFFDYRYSQADALKYVGIEREMEIP
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.
KEGG Pathway
MicroRNAs in cancer (hsa05206 )
Reactome Pathway
Oxidative Stress Induced Senescence (R-HSA-2559580 )
PKMTs methylate histone lysines (R-HSA-3214841 )
PRC2 methylates histones and DNA (R-HSA-212300 )
BioCyc Pathway
MetaCyc:HS02911-MON

Molecular Interaction Atlas (MIA) of This DTT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DTT
1 Approved Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
Tazemetostat DMWP1BH Follicular lymphoma 2A80 Approved [2]
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8 Clinical Trial Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
DS-3201b DMI69E5 T-cell leukaemia 2A90 Phase 2 [3]
CPI-0209 DMJEXLI Solid tumour/cancer 2A00-2F9Z Phase 1/2 [4]
CPI-1205 DM3XWJ8 Prostate cancer 2C82.0 Phase 1/2 [5]
SHR2554 DMMUCH0 Prostate cancer 2C82.0 Phase 1/2 [6]
DS-3201 DMRLPFG Acute lymphoblastic leukaemia 2A85 Phase 1 [5]
GSK2816126 DMJDVW4 Solid tumour/cancer 2A00-2F9Z Phase 1 [7]
HH2853 DMQIE58 Non-hodgkin lymphoma 2B33.5 Phase 1 [8]
PF-06821497 DML3WT6 Diffuse large B-cell lymphoma 2A81 Phase 1 [9]
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⏷ Show the Full List of 8 Clinical Trial Drug(s)
49 Patented Agent(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
PMID26882240-Compound-1 DMPAE8N N. A. N. A. Patented [10]
PMID28394193-Compound-12 DMA7H9T N. A. N. A. Patented [11]
PMID28394193-Compound-13 DMGZ9MW N. A. N. A. Patented [11]
PMID28394193-Compound-14 DM6T2FM N. A. N. A. Patented [11]
PMID28394193-Compound-15 DMXMP92 N. A. N. A. Patented [11]
PMID28394193-Compound-16 DMQDRUT N. A. N. A. Patented [11]
PMID28394193-Compound-17 DMPR9GA N. A. N. A. Patented [11]
PMID28394193-Compound-18 DMIBZ2H N. A. N. A. Patented [11]
PMID28394193-Compound-19 DM4ZAE8 N. A. N. A. Patented [11]
PMID28394193-Compound-20 DMC5NR0 N. A. N. A. Patented [11]
PMID28394193-Compound-21 DMLD8K3 N. A. N. A. Patented [11]
PMID28394193-Compound-22 DM8PJ3F N. A. N. A. Patented [11]
PMID28394193-Compound-23 DMNHCMY N. A. N. A. Patented [11]
PMID28394193-Compound-24 DMYCVWZ N. A. N. A. Patented [11]
PMID28394193-Compound-25 DMPIXAO N. A. N. A. Patented [11]
PMID28394193-Compound-26 DMNWCUJ N. A. N. A. Patented [11]
PMID28394193-Compound-27 DM2KVDH N. A. N. A. Patented [11]
PMID28394193-Compound-28 DMC24OL N. A. N. A. Patented [11]
PMID28394193-Compound-29 DMBVI7L N. A. N. A. Patented [11]
PMID28394193-Compound-30 DMGEZT8 N. A. N. A. Patented [11]
PMID28394193-Compound-31 DMJ02N1 N. A. N. A. Patented [11]
PMID28394193-Compound-32 DM628MP N. A. N. A. Patented [11]
PMID28394193-Compound-33 DMEOHX2 N. A. N. A. Patented [11]
PMID28394193-Compound-34 DMB7WNP N. A. N. A. Patented [11]
PMID28394193-Compound-36 DM658HJ N. A. N. A. Patented [11]
PMID28394193-Compound-37 DM73CA5 N. A. N. A. Patented [11]
PMID28394193-Compound-38 DM25PMQ N. A. N. A. Patented [11]
PMID28394193-Compound-39 DM2NS5T N. A. N. A. Patented [11]
PMID28394193-Compound-40 DMO5479 N. A. N. A. Patented [11]
PMID28394193-Compound-41 DMYLVTQ N. A. N. A. Patented [11]
PMID28394193-Compound-42 DMLI7TG N. A. N. A. Patented [11]
PMID28394193-Compound-43 DMASV8I N. A. N. A. Patented [11]
PMID28394193-Compound-44 DME6FWY N. A. N. A. Patented [11]
PMID28394193-Compound-45 DMZJXPF N. A. N. A. Patented [11]
PMID28394193-Compound-46 DMYMPNA N. A. N. A. Patented [11]
PMID28394193-Compound-47 DM7UDIM N. A. N. A. Patented [11]
PMID28394193-Compound-49 DMEU4Y1 N. A. N. A. Patented [11]
PMID28394193-Compound-50 DM4NVTB N. A. N. A. Patented [11]
PMID28394193-Compound-51 DM0KPQ9 N. A. N. A. Patented [11]
PMID28394193-Compound-52 DM2I9HY N. A. N. A. Patented [11]
PMID28394193-Compound-53 DMXMRQP N. A. N. A. Patented [11]
PMID28394193-Compound-54 DMMQ3UG N. A. N. A. Patented [11]
PMID28394193-Compound-55 DM2FPHZ N. A. N. A. Patented [11]
PMID28394193-Compound-56 DMQRFZK N. A. N. A. Patented [11]
PMID28394193-Compound-57 DM4Y3US N. A. N. A. Patented [11]
PMID28394193-Compound-Figure3bI DMXK2GA N. A. N. A. Patented [11]
PMID28394193-Compound-Figure3bII DML6PE0 N. A. N. A. Patented [11]
PMID28394193-Compound-Figure3bIII DMUI385 N. A. N. A. Patented [11]
PMID28394193-Compound-Figure5aVIII DMKVRTM N. A. N. A. Patented [11]
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⏷ Show the Full List of 49 Patented Agent(s)
1 #N/A Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
#N/A DMV1AGC N. A. N. A. #N/A [11]
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5 Investigative Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
EI1 DMBQCMU Discovery agent N.A. Investigative [12]
EPZ005687 DMYISTE Discovery agent N.A. Investigative [13]
GSK343 DM9QU5Y Discovery agent N.A. Investigative [14]
MS1943 DMTPGQ3 Breast cancer 2C60-2C65 Investigative [6]
UNC1999 DMOPCBD Discovery agent N.A. Investigative [15]
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References

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.
2 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
3 Development of new agents for peripheral T-cell lymphoma. Expert Opin Biol Ther. 2019 Mar;19(3):197-209.
4 ClinicalTrials.gov (NCT04104776) A Study of CPI-0209 in Patients With Advanced Tumors. U.S. National Institutes of Health.
5 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
6 Epigenetics and beyond: targeting writers of protein lysine methylation to treat disease. Nat Rev Drug Discov. 2021 Apr;20(4):265-286.
7 National Cancer Institute Drug Dictionary (drug id 756211).
8 Clinical pipeline report, company report or official report of HaiHe Biopharma.
9 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. 2018 Feb 8;61(3):650-665.
10 Hypoxia-inducible factor (HIF) inhibitors: a patent survey (2011-2015).Expert Opin Ther Pat. 2016;26(3):309-22.
11 EZH2 inhibitors: a patent review (2014-2016).Expert Opin Ther Pat. 2017 Jul;27(7):797-813.
12 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.
13 A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol. 2012 Nov;8(11):890-6.
14 Identification of Potent, Selective, Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2. ACS Med Chem Lett. 2012 Oct 19;3(12):1091-6.
15 An orally bioavailable chemical probe of the Lysine Methyltransferases EZH2 and EZH1. ACS Chem Biol. 2013;8(6):1324-34.