Target Information
| Target General Information | Top | |||||
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| Target ID |
T88304
(Former ID: TTDNC00597)
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| Target Name |
DNA [cytosine-5]-methyltransferase 1 (DNMT1)
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| Synonyms |
MCMT; M.HsaI; Dnmt1; DNMT; DNA methyltransferase HsaI; DNA MTase HsaI; DNA (cytosine5)methyltransferase 1; DNA (cytosine-5)-methyltransferase 1; CXXCtype zinc finger protein 9; CXXC9; CXXC-type zinc finger protein 9; AIM
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| Gene Name |
DNMT1
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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 | Myelodysplastic syndrome [ICD-11: 2A37] | |||||
| 3 | Myeloproliferative neoplasm [ICD-11: 2A20] | |||||
| Function |
Preferentially methylates hemimethylated DNA. Associates with DNA replication sites in S phase maintaining the methylation pattern in the newly synthesized strand, that is essential for epigenetic inheritance. Associates with chromatin during G2 and M phases to maintain DNA methylation independently of replication. It is responsible for maintaining methylation patterns established in development. DNA methylation is coordinated with methylation of histones. Mediates transcriptional repression by direct binding to HDAC2. In association with DNMT3B and via the recruitment of CTCFL/BORIS, involved in activation of BAG1 gene expression by modulating dimethylation of promoter histone H3 at H3K4 and H3K9. Probably forms a corepressor complex required for activated KRAS-mediated promoter hypermethylation and transcriptional silencing of tumor suppressor genes (TSGs) or other tumor-related genes in colorectal cancer (CRC) cells. Also required to maintain a transcriptionally repressive state of genes in undifferentiated embryonic stem cells (ESCs). Associates at promoter regions of tumor suppressor genes (TSGs) leading to their gene silencing. Promotes tumor growth. Methylates CpG residues.
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| BioChemical Class |
Methyltransferase
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| UniProt ID | ||||||
| EC Number |
EC 2.1.1.37
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| Sequence |
MPARTAPARVPTLAVPAISLPDDVRRRLKDLERDSLTEKECVKEKLNLLHEFLQTEIKNQ
LCDLETKLRKEELSEEGYLAKVKSLLNKDLSLENGAHAYNREVNGRLENGNQARSEARRV GMADANSPPKPLSKPRTPRRSKSDGEAKPEPSPSPRITRKSTRQTTITSHFAKGPAKRKP QEESERAKSDESIKEEDKDQDEKRRRVTSRERVARPLPAEEPERAKSGTRTEKEEERDEK EEKRLRSQTKEPTPKQKLKEEPDREARAGVQADEDEDGDEKDEKKHRSQPKDLAAKRRPE EKEPEKVNPQISDEKDEDEKEEKRRKTTPKEPTEKKMARAKTVMNSKTHPPKCIQCGQYL DDPDLKYGQHPPDAVDEPQMLTNEKLSIFDANESGFESYEALPQHKLTCFSVYCKHGHLC PIDTGLIEKNIELFFSGSAKPIYDDDPSLEGGVNGKNLGPINEWWITGFDGGEKALIGFS TSFAEYILMDPSPEYAPIFGLMQEKIYISKIVVEFLQSNSDSTYEDLINKIETTVPPSGL NLNRFTEDSLLRHAQFVVEQVESYDEAGDSDEQPIFLTPCMRDLIKLAGVTLGQRRAQAR RQTIRHSTREKDRGPTKATTTKLVYQIFDTFFAEQIEKDDREDKENAFKRRRCGVCEVCQ QPECGKCKACKDMVKFGGSGRSKQACQERRCPNMAMKEADDDEEVDDNIPEMPSPKKMHQ GKKKKQNKNRISWVGEAVKTDGKKSYYKKVCIDAETLEVGDCVSVIPDDSSKPLYLARVT ALWEDSSNGQMFHAHWFCAGTDTVLGATSDPLELFLVDECEDMQLSYIHSKVKVIYKAPS ENWAMEGGMDPESLLEGDDGKTYFYQLWYDQDYARFESPPKTQPTEDNKFKFCVSCARLA EMRQKEIPRVLEQLEDLDSRVLYYSATKNGILYRVGDGVYLPPEAFTFNIKLSSPVKRPR KEPVDEDLYPEHYRKYSDYIKGSNLDAPEPYRIGRIKEIFCPKKSNGRPNETDIKIRVNK FYRPENTHKSTPASYHADINLLYWSDEEAVVDFKAVQGRCTVEYGEDLPECVQVYSMGGP NRFYFLEAYNAKSKSFEDPPNHARSPGNKGKGKGKGKGKPKSQACEPSEPEIEIKLPKLR TLDVFSGCGGLSEGFHQAGISDTLWAIEMWDPAAQAFRLNNPGSTVFTEDCNILLKLVMA GETTNSRGQRLPQKGDVEMLCGGPPCQGFSGMNRFNSRTYSKFKNSLVVSFLSYCDYYRP RFFLLENVRNFVSFKRSMVLKLTLRCLVRMGYQCTFGVLQAGQYGVAQTRRRAIILAAAP GEKLPLFPEPLHVFAPRACQLSVVVDDKKFVSNITRLSSGPFRTITVRDTMSDLPEVRNG ASALEISYNGEPQSWFQRQLRGAQYQPILRDHICKDMSALVAARMRHIPLAPGSDWRDLP NIEVRLSDGTMARKLRYTHHDRKNGRSSSGALRGVCSCVEAGKACDPAARQFNTLIPWCL PHTGNRHNHWAGLYGRLEWDGFFSTTVTNPEPMGKQGRVLHPEQHRVVSVRECARSQGFP DTYRLFGNILDKHRQVGNAVPPPLAKAIGLEIKLCMLAKARESASAKIKEEEAAKD Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| ADReCS ID | BADD_A02700 | |||||
| HIT2.0 ID | T27LA6 | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 7 Clinical Trial Drugs | + | ||||
| 1 | CC-486 | Drug Info | Phase 3 | Myelodysplastic syndrome | [2] | |
| 2 | Guadecitabine | Drug Info | Phase 3 | Myelodysplastic syndrome | [3] | |
| 3 | S-110 | Drug Info | Phase 3 | Acute myeloid leukaemia | [3], [4] | |
| 4 | SGI110 | Drug Info | Phase 3 | Acute myeloid leukaemia | [4] | |
| 5 | Antroquinonol | Drug Info | Phase 2 | Non-small-cell lung cancer | [5] | |
| 6 | Palifosfamide | Drug Info | Phase 2 | Soft tissue sarcoma | [6] | |
| 7 | RX-3117 | Drug Info | Phase 2 | Bladder cancer | [3] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 24 Inhibitor drugs | + | ||||
| 1 | CC-486 | Drug Info | [7] | |||
| 2 | Guadecitabine | Drug Info | [3] | |||
| 3 | S-110 | Drug Info | [1] | |||
| 4 | Antroquinonol | Drug Info | [9] | |||
| 5 | Palifosfamide | Drug Info | [10] | |||
| 6 | RX-3117 | Drug Info | [11] | |||
| 7 | PMID27376512-Compound-asCEBP-1 | Drug Info | [12] | |||
| 8 | PMID27376512-Compound-asCEBP-1HPE | Drug Info | [12] | |||
| 9 | PMID27376512-Compound-asCEBP-2 | Drug Info | [12] | |||
| 10 | PMID27376512-Compound-asCEBP-2HPE | Drug Info | [12] | |||
| 11 | PMID27376512-Compound-miR-155-5p | Drug Info | [12] | |||
| 12 | PMID27376512-Compound-MTC-422 | Drug Info | [12] | |||
| 13 | PMID27376512-Compound-MTC-423 | Drug Info | [12] | |||
| 14 | PMID27376512-Compound-MTC-424 | Drug Info | [12] | |||
| 15 | PMID27376512-Compound-MTC-427 | Drug Info | [12] | |||
| 16 | PMID27376512-Compound-MTC-433 | Drug Info | [12] | |||
| 17 | PMID27376512-Compound-Table1Example11 | Drug Info | [12] | |||
| 18 | PMID27376512-Compound-Table1Example16 | Drug Info | [12] | |||
| 19 | PMID27376512-Compound-Table1Example30 | Drug Info | [12] | |||
| 20 | PMID27376512-Compound-Table1Example4 | Drug Info | [12] | |||
| 21 | PMID27376512-Compound-Table1Example5 | Drug Info | [12] | |||
| 22 | PMID27376512-Compound-Table1Example8 | Drug Info | [12] | |||
| 23 | CP-4200 | Drug Info | [13] | |||
| 24 | XB-05 | Drug Info | [13] | |||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | SGI110 | Drug Info | [8] | |||
| 2 | PMX-700 | Drug Info | [13] | |||
| 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 | |||||
|---|---|---|---|---|---|---|
| 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-regulating Transcription Factors | ||||||
| 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 | [+] 3 KEGG Pathways | + | ||||
| 1 | Cysteine and methionine metabolism | |||||
| 2 | Metabolic pathways | |||||
| 3 | MicroRNAs in cancer | |||||
| Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
| 1 | Methionine Metabolism | |||||
| PID Pathway | [+] 1 PID Pathways | + | ||||
| 1 | Regulation of retinoblastoma protein | |||||
| Reactome | [+] 3 Reactome Pathways | + | ||||
| 1 | PRC2 methylates histones and DNA | |||||
| 2 | NoRC negatively regulates rRNA expression | |||||
| 3 | DNA methylation | |||||
| WikiPathways | [+] 4 WikiPathways | + | ||||
| 1 | Trans-sulfuration and one carbon metabolism | |||||
| 2 | Retinoblastoma (RB) in Cancer | |||||
| 3 | One Carbon Metabolism | |||||
| 4 | Trans-sulfuration pathway | |||||
| References | Top | |||||
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| REF 1 | S110, a 5-Aza-2'-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth. Mol Cancer Ther. 2010 May;9(5):1443-50. | |||||
| REF 2 | J Clin Oncol 33, 2015 (suppl, abstr TPS7097). | |||||
| REF 3 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 4 | ClinicalTrials.gov (NCT02348489) SGI-110 in Adults With Untreated Acute Myeloid Leukemia (AML), Not Considered Candidates for Intensive Remission Induction. U.S. National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT02047344) Efficacy, Safety and Pharmacokinetics Study of Antroquinonol to Treat NSCLC. U.S. National Institutes of Health. | |||||
| REF 6 | ClinicalTrials.gov (NCT01808534) Palifosfamide in Treating Patients With Recurrent Germ Cell Tumors. U.S. National Institutes of Health. | |||||
| REF 7 | Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes. Leukemia. 2016 Apr;30(4):889-96. | |||||
| REF 8 | Immunomodulatory action of the DNA methyltransferase inhibitor SGI-110 in epithelial ovarian cancer cells and xenografts. Epigenetics. 2015;10(3):237-46. | |||||
| REF 9 | Antroquinonol D, isolated from Antrodia camphorata, with DNA demethylation and anticancer potential. J Agric Food Chem. 2014 Jun 18;62(24):5625-35. | |||||
| REF 10 | Anticancer activity of stabilized palifosfamide in vivo: schedule effects, oral bioavailability, and enhanced activity with docetaxel and doxorubicin. Anticancer Drugs. 2012 Feb;23(2):173-84. | |||||
| REF 11 | Metabolism, mechanism of action and sensitivity profile of fluorocyclopentenylcytosine (RX-3117; TV-1360). Invest New Drugs. 2013 Dec;31(6):1444-57. | |||||
| REF 12 | DNA methyltransferase inhibitors: an updated patent review (2012-2015).Expert Opin Ther Pat. 2016 Sep;26(9):1017-30. | |||||
| REF 13 | 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. (Target id: 2605). | |||||
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