Target Information
| Target General Information | Top | |||||
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| Target ID |
T87686
(Former ID: TTDNC00492)
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| Target Name |
Histone-lysine N-methyltransferase (HLNM)
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| Synonyms |
Lysine N-methyltransferase 4; KMT4; KIAA1814; Histone-lysine N-methyltransferase, H3 lysine-79 specific; Histone H3-K79 methyltransferase; H3-K79-HMTase; DOT1-like protein
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| Gene Name |
DOT1L
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Acute myeloid leukaemia [ICD-11: 2A60] | |||||
| 2 | Malignant haematopoietic neoplasm [ICD-11: 2B33] | |||||
| 3 | Mature B-cell lymphoma [ICD-11: 2A85] | |||||
| Function |
Histone methyltransferase. Methylates 'Lys-79' of histone H3. Nucleosomes are preferred as substrate compared to free histones. Binds to DNA.
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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 |
MGEKLELRLKSPVGAEPAVYPWPLPVYDKHHDAAHEIIETIRWVCEEIPDLKLAMENYVL
IDYDTKSFESMQRLCDKYNRAIDSIHQLWKGTTQPMKLNTRPSTGLLRHILQQVYNHSVT DPEKLNNYEPFSPEVYGETSFDLVAQMIDEIKMTDDDLFVDLGSGVGQVVLQVAAATNCK HHYGVEKADIPAKYAETMDREFRKWMKWYGKKHAEYTLERGDFLSEEWRERIANTSVIFV NNFAFGPEVDHQLKERFANMKEGGRIVSSKPFAPLNFRINSRNLSDIGTIMRVVELSPLK GSVSWTGKPVSYYLHTIDRTILENYFSSLKNPKLREEQEAARRRQQRESKSNAATPTKGP EGKVAGPADAPMDSGAEEEKAGAATVKKPSPSKARKKKLNKKGRKMAGRKRGRPKKMNTA NPERKPKKNQTALDALHAQTVSQTAASSPQDAYRSPHSPFYQLPPSVQRHSPNPLLVAPT PPALQKLLESFKIQYLQFLAYTKTPQYKASLQELLGQEKEKNAQLLGAAQQLLSHCQAQK EEIRRLFQQKLDELGVKALTYNDLIQAQKEISAHNQQLREQSEQLEQDNRALRGQSLQLL KARCEELQLDWATLSLEKLLKEKQALKSQISEKQRHCLELQISIVELEKSQRQQELLQLK SCVPPDDALSLHLRGKGALGRELEPDASRLHLELDCTKFSLPHLSSMSPELSMNGQAAGY ELCGVLSRPSSKQNTPQYLASPLDQEVVPCTPSHVGRPRLEKLSGLAAPDYTRLSPAKIV LRRHLSQDHTVPGRPAASELHSRAEHTKENGLPYQSPSVPGSMKLSPQDPRPLSPGALQL AGEKSSEKGLRERAYGSSGELITSLPISIPLSTVQPNKLPVSIPLASVVLPSRAERARST PSPVLQPRDPSSTLEKQIGANAHGAGSRSLALAPAGFSYAGSVAISGALAGSPASLTPGA EPATLDESSSSGSLFATVGSRSSTPQHPLLLAQPRNSLPASPAHQLSSSPRLGGAAQGPL PEASKGDLPSDSGFSDPESEAKRRIVFTITTGAGSAKQSPSSKHSPLTASARGDCVPSHG QDSRRRGRRKRASAGTPSLSAGVSPKRRALPSVAGLFTQPSGSPLNLNSMVSNINQPLEI TAISSPETSLKSSPVPYQDHDQPPVLKKERPLSQTNGAHYSPLTSDEEPGSEDEPSSARI ERKIATISLESKSPPKTLENGGGLAGRKPAPAGEPVNSSKWKSTFSPISDIGLAKSADSP LQASSALSQNSLFTFRPALEEPSADAKLAAHPRKGFPGSLSGADGLSPGTNPANGCTFGG GLAADLSLHSFSDGASLPHKGPEAAGLSSPLSFPSQRGKEGSDANPFLSKRQLDGLAGLK GEGSRGKEAGEGGLPLCGPTDKTPLLSGKAAKARDREVDLKNGHNLFISAAAVPPGSLLS GPGLAPAASSAGGAASSAQTHRSFLGPFPPGPQFALGPMSLQANLGSVAGSSVLQSLFSS VPAAAGLVHVSSAATRLTNSHAMGSFSGVAGGTVGGN Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T98O63 | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | EPZ-5676 | Drug Info | Phase 1/2 | Acute myeloid leukaemia | [2] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | EPZ-5676 | Drug Info | [1] | |||
| Inhibitor | [+] 3 Inhibitor drugs | + | ||||
| 1 | bromo-deaza-SAH | Drug Info | [3] | |||
| 2 | EPZ-004777 | Drug Info | [4] | |||
| 3 | SGC0946 | Drug Info | [5] | |||
| 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 | DOT1L Structure in complex with SAM | PDB:3QOW | ||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [6] |
| PDB Sequence |
KLELRLKSPV
13 GAEPAVYPWP23 LPVYDKHHDA33 AHEIIETIRW43 VCEEIPDLKL53 AMENYLIDYD 64 TKSFESMQRL74 CDKYNRAIDS84 IHQLWKGTTQ94 PMKLNTRPST104 GLLRHILQQV 114 YNHSVTDPEK124 LNNYEPFSPE134 VYGETSFDLV144 AQMIDEIKMT154 DDDLFVDLGS 164 GVGQVVLQVA174 AATNCKHHYG184 VEKADIPAKY194 AETMDREFRK204 WMKWYGKKHA 214 EYTLERGDFL224 SEEWRERIAN234 TSVIFVNNFA244 FGPEVDHQLK254 ERFANMKEGG 264 RIVSSKPFAP274 LNFRINSRNL284 SDIGTIMRVV294 ELSPLKWTGK308 PVSYYLHTID 318 RTILENYFSS328 LK
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PRO133
3.163
GLU134
4.051
VAL135
3.296
TYR136
3.841
GLY137
3.180
GLU138
3.219
THR139
2.671
ASP161
2.866
LEU162
4.797
GLY163
2.742
SER164
3.661
GLY165
4.023
GLN168
3.000
VAL169
3.685
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Adenosine | Ligand Info | |||||
| Structure Description | Crystal structure of Dot1L in complex with adenosine and inhibitor CPD1 [N6-(2,6-dichlorophenyl)-N6-(pent-2-yn-1-yl)quinoline-4,6-diamine] | PDB:5MVS | ||||
| Method | X-ray diffraction | Resolution | 2.18 Å | Mutation | No | [7] |
| PDB Sequence |
LELRLKSPVG
14 AEPAVYPWPL24 PVYDKHHDAA34 HEIIETIRWV44 CEEIPDLKLA54 MENYVLIDYD 64 TKSFESMQRL74 CDKYNRAIDS84 IHQLWKGTNT100 RPSTGLLRHI110 LQQVYNHSVT 120 DPEKLNNYEP130 FSPEVYGETS140 FDLVAQMIDE150 IKMTDDDLFV160 DLGSGVGQVV 170 LQVAAATNCK180 HHYGVEKADI190 PAKYAETMDR200 EFRKWMKWYG210 KKHAEYTLER 220 GDFLSEEWRE230 RIANTSVIFV240 NNFAFGPEVD250 HQLKERFANM260 KEGGRIVSSK 270 PFAPLNFRIN280 SRNLSDIGTI290 MRVVELSPLK300 GSWTGKPVSY312 YLHTIDRTIL 322 ENYFSSLKNP332
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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 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 Pathway Affiliation
Biological Network Descriptors
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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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| Septin-14 (SEPTIN14) | 25.564 (34/133) | 3.00E-03 |
| 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 | 7 | Degree centrality | 7.52E-04 | Betweenness centrality | 2.20E-04 |
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| Closeness centrality | 1.91E-01 | Radiality | 1.33E+01 | Clustering coefficient | 2.86E-01 |
| Neighborhood connectivity | 1.43E+01 | Topological coefficient | 1.99E-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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| 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 | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | Lysine degradation | |||||
| 2 | Transcriptional misregulation in cancer | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | PKMTs methylate histone lysines | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Histone Modifications | |||||
| References | Top | |||||
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| REF 1 | Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood. 2013 August 8; 122(6): 1017-1025. | |||||
| REF 2 | ClinicalTrials.gov (NCT03701295) Pinometostat and Azacitidine in Treating Patients With Relapsed, Refractory, or Newly Diagnosed Acute Myeloid Leukemia With 11q23 Rearrangement. U.S. National Institutes of Health. | |||||
| REF 3 | Bromo-deaza-SAH: a potent and selective DOT1L inhibitor. Bioorg Med Chem. 2013 Apr 1;21(7):1787-94. | |||||
| REF 4 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7377). | |||||
| REF 5 | Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nat Commun. 2012;3:1288. | |||||
| REF 6 | Chemogenetic analysis of human protein methyltransferases. Chem Biol Drug Des. 2011 Aug;78(2):199-210. | |||||
| REF 7 | Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach. ACS Med Chem Lett. 2017 Feb 14;8(3):338-343. | |||||
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