Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT6S2FE)

• DTT Name: DNA [cytosine-5]-methyltransferase 1 (DNMT1)
• 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
• Gene Name: DNMT1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Methyltransferase
• UniProt ID: DNMT1_HUMAN
• TTD ID: T88304
• 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
• 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.
• KEGG Pathway:
  Cysteine and methionine metabolism (hsa00270)
  Metabolic pathways (hsa01100)
  MicroRNAs in cancer (hsa05206)
• Reactome Pathway:
  NoRC negatively regulates rRNA expression (R-HSA-427413)
  DNA methylation (R-HSA-5334118)
  PRC2 methylates histones and DNA (R-HSA-212300)

Molecular Interaction Atlas (MIA) of This DTT

8 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CC-486	DMTNQB0	Acute myeloid leukaemia	2A60	Phase 3	[2]
Guadecitabine	DM9Y3EG	Myelodysplastic syndrome	2A37	Phase 3	[3]
S-110	DMXY34J	Acute myeloid leukaemia	2A60	Phase 3	[1]
SGI110	DM1NQDW	Acute myeloid leukaemia	2A60	Phase 3	[4]
Antroquinonol	DMRGQVZ	Non-small-cell lung cancer	2C25.Y	Phase 2	[5]
Palifosfamide	DMMIYZ7	Soft tissue sarcoma	2B57	Phase 2	[6]
RX-3117	DME8ARP	Bladder cancer	2C94	Phase 2	[7]
GSK4172239	DM930LE	Sickle-cell disorder	3A51	Phase 1	[8]

16 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID27376512-Compound-asCEBP-1	DMTQRVC	N. A.	N. A.	Patented	[9]
PMID27376512-Compound-asCEBP-1HPE	DMLAY8B	N. A.	N. A.	Patented	[9]
PMID27376512-Compound-asCEBP-2	DMJUL1A	N. A.	N. A.	Patented	[9]
PMID27376512-Compound-asCEBP-2HPE	DM9QEIV	N. A.	N. A.	Patented	[9]
PMID27376512-Compound-miR-155-5p	DM67VNW	N. A.	N. A.	Patented	[9]
PMID27376512-Compound-MTC-422	DM1MVQD	N. A.	N. A.	Patented	[9]
PMID27376512-Compound-MTC-423	DM9RSDX	N. A.	N. A.	Patented	[9]
PMID27376512-Compound-MTC-424	DMGNRZU	N. A.	N. A.	Patented	[9]
PMID27376512-Compound-MTC-427	DMWXEZD	N. A.	N. A.	Patented	[9]
PMID27376512-Compound-MTC-433	DM7OS5E	N. A.	N. A.	Patented	[9]
PMID27376512-Compound-Table1Example11	DMIFTUN	N. A.	N. A.	Patented	[9]
PMID27376512-Compound-Table1Example16	DMM3VA8	N. A.	N. A.	Patented	[9]
PMID27376512-Compound-Table1Example30	DM5RX9D	N. A.	N. A.	Patented	[9]
PMID27376512-Compound-Table1Example4	DMFJG7P	N. A.	N. A.	Patented	[9]
PMID27376512-Compound-Table1Example5	DM4Q6XZ	N. A.	N. A.	Patented	[9]
PMID27376512-Compound-Table1Example8	DMKU7GD	N. A.	N. A.	Patented	[9]

3 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CP-4200	DMZMKAQ	Solid tumour/cancer	2A00-2F9Z	Investigative	[10]
PMX-700	DMZCSF1	Glioblastoma multiforme	2A00.0	Investigative	[10]
XB-05	DMYT5DI	Solid tumour/cancer	2A00-2F9Z	Investigative	[10]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Sarcoma	2C82	Muscle tissue	0.00E+00	2.46	4.65
Lung cancer	2C82	Lung tissue	1.56E-81	0.73	2.22
Acute myelocytic leukaemia	2C82	Bone marrow	6.48E-04	-0.11	-0.34
Myelodysplastic syndrome	2C82	Bone marrow	5.50E-01	0.09	0.32
Glioma	2C82	Brainstem tissue	2.06E-08	0.71	15.47
Glioma	2C82	White matter	1.27E-05	0.97	2.41

References

• [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.
• [2] 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.
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Immunomodulatory action of the DNA methyltransferase inhibitor SGI-110 in epithelial ovarian cancer cells and xenografts. Epigenetics. 2015;10(3):237-46.
• [5] Antroquinonol D, isolated from Antrodia camphorata, with DNA demethylation and anticancer potential. J Agric Food Chem. 2014 Jun 18;62(24):5625-35.
• [6] 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.
• [7] Metabolism, mechanism of action and sensitivity profile of fluorocyclopentenylcytosine (RX-3117; TV-1360). Invest New Drugs. 2013 Dec;31(6):1444-57.
• [8] Clinical pipeline report, company report or official report of GlaxoSmithKline
• [9] DNA methyltransferase inhibitors: an updated patent review (2012-2015).Expert Opin Ther Pat. 2016 Sep;26(9):1017-30.
• [10] 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).