Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKKT03T)

• DOT Name: Methylcytosine dioxygenase TET2 (TET2)
• Synonyms: EC 1.14.11.80
• Gene Name: TET2
• Related Disease:
  Promyelocytic leukaemia
  Angioimmunoblastic T-cell Lymphoma
  Breast cancer
  Breast carcinoma
  Chronic myelomonocytic leukaemia
  Chronic myelomonocytic leukemia
  Chronic obstructive pulmonary disease
  Clear cell renal carcinoma
  Colorectal adenocarcinoma
  Colorectal adenoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal neoplasm
  Congestive heart failure
  Essential thrombocythemia
  High blood pressure
  Immunodeficiency 75
  Inflammatory bowel disease
  Mastocytosis
  Melanoma
  Multiple sclerosis
  Neoplasm
  Papillary renal cell carcinoma
  Renal cell carcinoma
  Schizophrenia
  Sezary syndrome
  Systemic mastocytosis
  T-cell lymphoma
  Colorectal carcinoma
  Pulmonary arterial hypertension
  Ulcerative colitis
  Acute monocytic leukemia
  Anemia
  Childhood myelodysplastic syndrome
  Colon cancer
  Haematological malignancy
  Leukemia
  Myelofibrosis
  Non-hodgkin lymphoma
  Primary cutaneous peripheral T-cell lymphoma not otherwise specified
  Prostate neoplasm
• UniProt ID: TET2_HUMAN
• PDB ID: 4NM6; 5D9Y; 5DEU; 7NE3; 7NE6
• EC Number: 1.14.11.80
• Pfam ID: PF12851
• Sequence:
  MEQDRTNHVEGNRLSPFLIPSPPICQTEPLATKLQNGSPLPERAHPEVNGDTKWHSFKSY
  YGIPCMKGSQNSRVSPDFTQESRGYSKCLQNGGIKRTVSEPSLSGLLQIKKLKQDQKANG
  ERRNFGVSQERNPGESSQPNVSDLSDKKESVSSVAQENAVKDFTSFSTHNCSGPENPELQ
  ILNEQEGKSANYHDKNIVLLKNKAVLMPNGATVSASSVEHTHGELLEKTLSQYYPDCVSI
  AVQKTTSHINAINSQATNELSCEITHPSHTSGQINSAQTSNSELPPKPAAVVSEACDADD
  ADNASKLAAMLNTCSFQKPEQLQQQKSVFEICPSPAENNIQGTTKLASGEEFCSGSSSNL
  QAPGGSSERYLKQNEMNGAYFKQSSVFTKDSFSATTTPPPPSQLLLSPPPPLPQVPQLPS
  EGKSTLNGGVLEEHHHYPNQSNTTLLREVKIEGKPEAPPSQSPNPSTHVCSPSPMLSERP
  QNNCVNRNDIQTAGTMTVPLCSEKTRPMSEHLKHNPPIFGSSGELQDNCQQLMRNKEQEI
  LKGRDKEQTRDLVPPTQHYLKPGWIELKAPRFHQAESHLKRNEASLPSILQYQPNLSNQM
  TSKQYTGNSNMPGGLPRQAYTQKTTQLEHKSQMYQVEMNQGQSQGTVDQHLQFQKPSHQV
  HFSKTDHLPKAHVQSLCGTRFHFQQRADSQTEKLMSPVLKQHLNQQASETEPFSNSHLLQ
  HKPHKQAAQTQPSQSSHLPQNQQQQQKLQIKNKEEILQTFPHPQSNNDQQREGSFFGQTK
  VEECFHGENQYSKSSEFETHNVQMGLEEVQNINRRNSPYSQTMKSSACKIQVSCSNNTHL
  VSENKEQTTHPELFAGNKTQNLHHMQYFPNNVIPKQDLLHRCFQEQEQKSQQASVLQGYK
  NRNQDMSGQQAAQLAQQRYLIHNHANVFPVPDQGGSHTQTPPQKDTQKHAALRWHLLQKQ
  EQQQTQQPQTESCHSQMHRPIKVEPGCKPHACMHTAPPENKTWKKVTKQENPPASCDNVQ
  QKSIIETMEQHLKQFHAKSLFDHKALTLKSQKQVKVEMSGPVTVLTRQTTAAELDSHTPA
  LEQQTTSSEKTPTKRTAASVLNNFIESPSKLLDTPIKNLLDTPVKTQYDFPSCRCVEQII
  EKDEGPFYTHLGAGPNVAAIREIMEERFGQKGKAIRIERVIYTGKEGKSSQGCPIAKWVV
  RRSSSEEKLLCLVRERAGHTCEAAVIVILILVWEGIPLSLADKLYSELTETLRKYGTLTN
  RRCALNEERTCACQGLDPETCGASFSFGCSWSMYYNGCKFARSKIPRKFKLLGDDPKEEE
  KLESHLQNLSTLMAPTYKKLAPDAYNNQIEYEHRAPECRLGLKEGRPFSGVTACLDFCAH
  AHRDLHNMQNGSTLVCTLTREDNREFGGKPEDEQLHVLPLYKVSDVDEFGSVEAQEEKKR
  SGAIQVLSSFRRKVRMLAEPVKTCRQRKLEAKKAAAEKLSSLENSSNKNEKEKSAPSRTK
  QTENASQAKQLAELLRLSGPVMQQSQQPQPLQKQPPQPQQQQRPQQQQPHHPQTESVNSY
  SASGSTNPYMRRPNPVSPYPNSSHTSDIYGSTSPMNFYSTSSQAAGSYLNSSNPMNPYPG
  LLNQNTQYPSYQCNGNLSVDNCSPYLGSYSPQSQPMDLYRYPSQDPLSKLSLPPIHTLYQ
  PRFGNSQSFTSKYLGYGNQNMQGDGFSSCTIRPNVHHVGKLPPYPTHEMDGHFMGATSRL
  PPNLSNPNMDYKNGEHHSPSHIIHNYSAAPGMFNSSLHALHLQNKENDMLSHTANGLSKM
  LPALNHDRTACVQGGLHKLSDANGQEKQPLALVQGVASGAEDNDEVWSDSEQSFLDPDIG
  GVAVAPTHGSILIECAKRELHATTPLKNPNRNHPTRISLVFYQHKSMNEPKHGLALWEAK
  MAEKAREKEEECEKYGPDYVPQKSHGKKVKREPAEPHETSEPTYLRFIKSLAERTMSVTT
  DSTVTTSPYAFTRVTGPYNRYI
• Function: Dioxygenase that catalyzes the conversion of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in active DNA demethylation. Has a preference for 5-hydroxymethylcytosine in CpG motifs. Also mediates subsequent conversion of 5hmC into 5-formylcytosine (5fC), and conversion of 5fC to 5-carboxylcytosine (5caC). Conversion of 5mC into 5hmC, 5fC and 5caC probably constitutes the first step in cytosine demethylation. Methylation at the C5 position of cytosine bases is an epigenetic modification of the mammalian genome which plays an important role in transcriptional regulation. In addition to its role in DNA demethylation, also involved in the recruitment of the O-GlcNAc transferase OGT to CpG-rich transcription start sites of active genes, thereby promoting histone H2B GlcNAcylation by OGT.
• Tissue Specificity: Broadly expressed. Highly expressed in hematopoietic cells; highest expression observed in granulocytes. Expression is reduced in granulocytes from peripheral blood of patients affected by myelodysplastic syndromes.
• Reactome Pathway:
  Specification of primordial germ cells (R-HSA-9827857)
  TET1,2,3 and TDG demethylate DNA (R-HSA-5221030)

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Promyelocytic leukaemia	DISYGG13	Definitive	Genetic Variation	[1]
Angioimmunoblastic T-cell Lymphoma	DISZPFTL	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Chronic myelomonocytic leukaemia	DISDN5P7	Strong	Biomarker	[4]
Chronic myelomonocytic leukemia	DISIL8UR	Strong	Biomarker	[5]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[6]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[7]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[8]
Colorectal adenoma	DISTSVHM	Strong	Genetic Variation	[8]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[8]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[8]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[8]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[8]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[8]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[9]
Essential thrombocythemia	DISWWK11	Strong	Genetic Variation	[10]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[9]
Immunodeficiency 75	DISDVWSC	Strong	Autosomal recessive	[11]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[12]
Mastocytosis	DIS1TEE0	Strong	Genetic Variation	[13]
Melanoma	DIS1RRCY	Strong	Biomarker	[14]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[15]
Neoplasm	DISZKGEW	Strong	Biomarker	[16]
Papillary renal cell carcinoma	DIS25HBV	Strong	Biomarker	[7]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[7]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[17]
Sezary syndrome	DISFMTC7	Strong	Biomarker	[18]
Systemic mastocytosis	DISNQ2OY	Strong	Genetic Variation	[19]
T-cell lymphoma	DISSXRTQ	Strong	Biomarker	[20]
Colorectal carcinoma	DIS5PYL0	moderate	Genetic Variation	[8]
Pulmonary arterial hypertension	DISP8ZX5	Moderate	Autosomal dominant	[21]
Ulcerative colitis	DIS8K27O	moderate	Genetic Variation	[22]
Acute monocytic leukemia	DIS28NEL	Limited	Biomarker	[23]
Anemia	DISTVL0C	Limited	Genetic Variation	[24]
Childhood myelodysplastic syndrome	DISMN80I	Limited	Genetic Variation	[25]
Colon cancer	DISVC52G	Limited	Biomarker	[26]
Haematological malignancy	DISCDP7W	Limited	Biomarker	[27]
Leukemia	DISNAKFL	Limited	Genetic Variation	[28]
Myelofibrosis	DISIMP21	Limited	Genetic Variation	[29]
Non-hodgkin lymphoma	DISS2Y8A	Limited	Genetic Variation	[30]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	DIS5OHQF	Limited	Genetic Variation	[31]
Prostate neoplasm	DISHDKGQ	Limited	Altered Expression	[32]

14 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Methylcytosine dioxygenase TET2 (TET2).	[33]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Methylcytosine dioxygenase TET2 (TET2).	[34]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Methylcytosine dioxygenase TET2 (TET2).	[35]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Methylcytosine dioxygenase TET2 (TET2).	[36]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Methylcytosine dioxygenase TET2 (TET2).	[38]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Methylcytosine dioxygenase TET2 (TET2).	[39]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Methylcytosine dioxygenase TET2 (TET2).	[40]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Methylcytosine dioxygenase TET2 (TET2).	[39]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Methylcytosine dioxygenase TET2 (TET2).	[42]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Methylcytosine dioxygenase TET2 (TET2).	[44]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Methylcytosine dioxygenase TET2 (TET2).	[36]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Methylcytosine dioxygenase TET2 (TET2).	[45]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Methylcytosine dioxygenase TET2 (TET2).	[46]
Dorsomorphin	DMKYXJW	Investigative	Dorsomorphin decreases the expression of Methylcytosine dioxygenase TET2 (TET2).	[47]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Methylcytosine dioxygenase TET2 (TET2).	[37]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Methylcytosine dioxygenase TET2 (TET2).	[41]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Methylcytosine dioxygenase TET2 (TET2).	[43]

References

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• [12] I_MDS: an inflammatory bowel disease molecular activity score to classify patients with differing disease-driving pathways and therapeutic response to anti-TNF treatment.PLoS Comput Biol. 2019 Apr 30;15(4):e1006951. doi: 10.1371/journal.pcbi.1006951. eCollection 2019 Apr.
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• [19] Next-generation sequencing in systemic mastocytosis: Derivation of a mutation-augmented clinical prognostic model for survival.Am J Hematol. 2016 Sep;91(9):888-93. doi: 10.1002/ajh.24426. Epub 2016 Jun 20.
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• [21] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
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• [29] Next-generation sequencing with a 54-gene panel identified unique mutational profile and prognostic markers in Chinese patients with myelofibrosis.Ann Hematol. 2019 Apr;98(4):869-879. doi: 10.1007/s00277-018-3563-7. Epub 2018 Dec 4.
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• [34] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
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