Target Information

Target General Infomation
Target ID
T88304
Former ID
TTDNC00597
Target Name
DNMT1
Gene Name
DNMT1
Synonyms
CXXCtype zinc finger protein 9; DNA (cytosine5)methyltransferase 1; DNA MTase HsaI; DNA methyltransferase HsaI; Dnmt1; M.HsaI; MCMT; DNMT1
Target Type
Clinical Trial
Disease Acute myeloid leukemia; Myelodysplastic syndrome [ICD9:205, 238.7; ICD10: C92.0, D46]
Acute myeloid leukemia [ICD9: 205; ICD10: C92.0]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Glioblastoma multiforme [ICD9: 191; ICD10: C71]
Late-stage solid tumors [ICD9: 140-199, 210-229; ICD10: C00-C75, C7A, C7B, D10-D36, D3A]
Myelodysplastic syndrome [ICD9: 238.7; ICD10: D46]
Non-small cell lung cancer [ICD10: C33-C34]
Soft tissue sarcoma [ICD9: 171; ICD10: C00-D49]
Function
Methylates CpG residues. 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 methylationis 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.
BioChemical Class
Methyltransferase superfamily
UniProt ID
P26358
EC Number
EC 2.1.1.37
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
Drugs and Mode of Action
Drug(s) CC-486 Drug Info Phase 3 Myelodysplastic syndrome [549703]
S-110 Drug Info Phase 3 Acute myeloid leukemia [525074]
SGI110 Drug Info Phase 3 Acute myeloid leukemia; Myelodysplastic syndrome [525074]
Antroquinonol Drug Info Phase 2 Non-small cell lung cancer [524616]
Palifosfamide Drug Info Phase 2 Soft tissue sarcoma [524236]
Oral azacitidine Drug Info Phase 1 Myelodysplastic syndrome [524889], [531480]
RX-3117 Drug Info Phase 1 Late-stage solid tumors [524590]
Inhibitor Antroquinonol Drug Info [532758]
CC-486 Drug Info [533326]
CP-4200 Drug Info [543657]
Oral azacitidine Drug Info [528903]
Palifosfamide Drug Info [531674]
RX-3117 Drug Info [532483]
S-110 Drug Info [530893]
XB-05 Drug Info [543657]
Modulator PMX-700 Drug Info [543657]
SGI110 Drug Info [533185]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Cysteine and methionine metabolism
Metabolic pathways
MicroRNAs in cancer
Pathway Interaction Database Regulation of retinoblastoma protein
PathWhiz Pathway Methionine Metabolism
Reactome PRC2 methylates histones and DNA
NoRC negatively regulates rRNA expression
DNA methylation
WikiPathways Trans-sulfuration and one carbon metabolism
Retinoblastoma (RB) in Cancer
One Carbon Metabolism
Trans-sulfuration pathway
References
Ref 524236ClinicalTrials.gov (NCT01808534) Palifosfamide in Treating Patients With Recurrent Germ Cell Tumors. U.S. National Institutes of Health.
Ref 524590ClinicalTrials.gov (NCT02030067) Dose-Finding and Safety Study for Oral Single-Agent to Treat Advanced Malignancies. U.S. National Institutes of Health.
Ref 524616ClinicalTrials.gov (NCT02047344) Efficacy, Safety and Pharmacokinetics Study of Antroquinonol to Treat NSCLC. U.S. National Institutes of Health.
Ref 524889ClinicalTrials.gov (NCT02223052) CC-486 (Oral Azacitidine) Bioequivalence Study in Patients With Solid Tumor or Hematologic Malignancies. U.S. National Institutes of Health.
Ref 525074ClinicalTrials.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 531480Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. J Clin Oncol. 2011 Jun 20;29(18):2521-7.
Ref 549703J Clin Oncol 33, 2015 (suppl, abstr TPS7097).
Ref 5289035-Azacytidine, a DNA methyltransferase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells. Mol Cancer Ther. 2007 Jun;6(6):1718-27.
Ref 530893S110, 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 531674Anticancer 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 532483Metabolism, mechanism of action and sensitivity profile of fluorocyclopentenylcytosine (RX-3117; TV-1360). Invest New Drugs. 2013 Dec;31(6):1444-57.
Ref 532758Antroquinonol D, isolated from Antrodia camphorata, with DNA demethylation and anticancer potential. J Agric Food Chem. 2014 Jun 18;62(24):5625-35.
Ref 533185Immunomodulatory action of the DNA methyltransferase inhibitor SGI-110 in epithelial ovarian cancer cells and xenografts. Epigenetics. 2015;10(3):237-46.
Ref 533326Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes. Leukemia. 2015 Oct 7.
Ref 543657(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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