Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ6SW4R)

• DOT Name: Histone-lysine N-methyltransferase NSD2 (NSD2)
• Synonyms: EC 2.1.1.357; Multiple myeloma SET domain-containing protein; MMSET; Nuclear SET domain-containing protein 2; Protein trithorax-5; Wolf-Hirschhorn syndrome candidate 1 protein
• Gene Name: NSD2
• Related Disease:
  Childhood acute lymphoblastic leukemia
  Syndromic intellectual disability
  Wolf-Hirschhorn syndrome
  Acute lymphocytic leukaemia
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cardiac failure
  Cardiovascular disease
  Chromosomal disorder
  Colorectal carcinoma
  Congestive heart failure
  Endometrial cancer
  Endometrial carcinoma
  Epithelial ovarian cancer
  Fetal growth restriction
  Gastric cancer
  Head-neck squamous cell carcinoma
  Intellectual disability
  Intrahepatic cholangiocarcinoma
  Isolated congenital microcephaly
  Leukemia
  Lung cancer
  Lung carcinoma
  Mantle cell lymphoma
  Metastatic malignant neoplasm
  Metastatic prostate carcinoma
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Rauch-Steindl syndrome
  Stomach cancer
  Trichohepatoenteric syndrome
  Triple negative breast cancer
  Cervical cancer
  Cervical carcinoma
  Clear cell renal carcinoma
  Hepatocellular carcinoma
  High blood pressure
  Kidney cancer
  Neoplasm
  Renal carcinoma
  Renal cell carcinoma
  Advanced cancer
  Cutaneous squamous cell carcinoma
  Non-insulin dependent diabetes
• UniProt ID: NSD2_HUMAN
• PDB ID: 5LSU; 5VC8; 6UE6; 6XCG; 7CRO; 7E8D; 7LMT; 7MDN; 7VLN
• EC Number: 2.1.1.357
• Pfam ID: PF17907 ; PF17982 ; PF00505 ; PF00628 ; PF00855 ; PF00856
• Sequence:
  MEFSIKQSPLSVQSVVKCIKMKQAPEILGSANGKTPSCEVNRECSVFLSKAQLSSSLQEG
  VMQKFNGHDALPFIPADKLKDLTSRVFNGEPGAHDAKLRFESQEMKGIGTPPNTTPIKNG
  SPEIKLKITKTYMNGKPLFESSICGDSAADVSQSEENGQKPENKARRNRKRSIKYDSLLE
  QGLVEAALVSKISSPSDKKIPAKKESCPNTGRDKDHLLKYNVGDLVWSKVSGYPWWPCMV
  SADPLLHSYTKLKGQKKSARQYHVQFFGDAPERAWIFEKSLVAFEGEGQFEKLCQESAKQ
  APTKAEKIKLLKPISGKLRAQWEMGIVQAEEAASMSVEERKAKFTFLYVGDQLHLNPQVA
  KEAGIAAESLGEMAESSGVSEEAAENPKSVREECIPMKRRRRAKLCSSAETLESHPDIGK
  STPQKTAEADPRRGVGSPPGRKKTTVSMPRSRKGDAASQFLVFCQKHRDEVVAEHPDASG
  EEIEELLRSQWSLLSEKQRARYNTKFALVAPVQAEEDSGNVNGKKRNHTKRIQDPTEDAE
  AEDTPRKRLRTDKHSLRKRDTITDKTARTSSYKAMEAASSLKSQAATKNLSDACKPLKKR
  NRASTAASSALGFSKSSSPSASLTENEVSDSPGDEPSESPYESADETQTEVSVSSKKSER
  GVTAKKEYVCQLCEKPGSLLLCEGPCCGAFHLACLGLSRRPEGRFTCSECASGIHSCFVC
  KESKTDVKRCVVTQCGKFYHEACVKKYPLTVFESRGFRCPLHSCVSCHASNPSNPRPSKG
  KMMRCVRCPVAYHSGDACLAAGCSVIASNSIICTAHFTARKGKRHHAHVNVSWCFVCSKG
  GSLLCCESCPAAFHPDCLNIEMPDGSWFCNDCRAGKKLHFQDIIWVKLGNYRWWPAEVCH
  PKNVPPNIQKMKHEIGEFPVFFFGSKDYYWTHQARVFPYMEGDRGSRYQGVRGIGRVFKN
  ALQEAEARFREIKLQREARETQESERKPPPYKHIKVNKPYGKVQIYTADISEIPKCNCKP
  TDENPCGFDSECLNRMLMFECHPQVCPAGEFCQNQCFTKRQYPETKIIKTDGKGWGLVAK
  RDIRKGEFVNEYVGELIDEEECMARIKHAHENDITHFYMLTIDKDRIIDAGPKGNYSRFM
  NHSCQPNCETLKWTVNGDTRVGLFAVCDIPAGTELTFNYNLDCLGNEKTVCRCGASNCSG
  FLGDRPKTSTTLSSEEKGKKTKKKTRRRRAKGEGKRQSEDECFRCGDGGQLVLCDRKFCT
  KAYHLSCLGLGKRPFGKWECPWHHCDVCGKPSTSFCHLCPNSFCKEHQDGTAFSCTPDGR
  SYCCEHDLGAASVRSTKTEKPPPEPGKPKGKRRRRRGWRRVTEGK
• Function: Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at 'Lys-36' (H3K36me2). Also monomethylates nucleosomal histone H3 at 'Lys-36' (H3K36me) in vitro. Does not trimethylate nucleosomal histone H3 at 'Lys-36' (H3K36me3). However, specifically trimethylates histone H3 at 'Lys-36' (H3K36me3) at euchromatic regions in embryonic stem (ES) cells. By methylating histone H3 at 'Lys-36', involved in the regulation of gene transcription during various biological processes. In ES cells, associates with developmental transcription factors such as SALL1 and represses inappropriate gene transcription mediated by histone deacetylation. During heart development, associates with transcription factor NKX2-5 to repress transcription of NKX2-5 target genes. Plays an essential role in adipogenesis, by regulating expression of genes involved in pre-adipocyte differentiation. During T-cell receptor (TCR) and CD28-mediated T-cell activation, promotes the transcription of transcription factor BCL6 which is required for follicular helper T (Tfh) cell differentiation. During B-cell development, required for the generation of the B1 lineage. During B2 cell activation, may contribute to the control of isotype class switch recombination (CRS), splenic germinal center formation, and the humoral immune response. Plays a role in class switch recombination of the immunoglobulin heavy chain (IgH) locus during B-cell activation. By regulating the methylation of histone H3 at 'Lys-36' and histone H4 at 'Lys-20' at the IgH locus, involved in TP53BP1 recruitment to the IgH switch region and promotes the transcription of IgA; [Isoform 1]: Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at 'Lys-36' (H3K36me2); [Isoform 4]: Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at 'Lys-36' (H3K36me2). Methylation of histone H3 at 'Lys-27' is controversial. Mono-, di- or tri-methylates histone H3 at 'Lys-27' (H3K27me, H3K27me2 and H3K27me3). Does not methylate histone H3 at 'Lys-27'. May act as a transcription regulator that binds DNA and suppresses IL5 transcription through HDAC recruitment.
• Tissue Specificity: Widely expressed . Predominantly expressed in thymus and testis .
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Metabolic pathways (hsa01100)
  Transcriptio.l misregulation in cancer (hsa05202)
• Reactome Pathway:
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  Nonhomologous End-Joining (NHEJ) (R-HSA-5693571)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  G2/M DNA damage checkpoint (R-HSA-69473)
  PKMTs methylate histone lysines (R-HSA-3214841)
• BioCyc Pathway: MetaCyc:HS03249-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Childhood acute lymphoblastic leukemia	DISJ5D6U	Definitive	Genetic Variation	[1]
Syndromic intellectual disability	DISH7SDF	Definitive	Autosomal dominant	[2]
Wolf-Hirschhorn syndrome	DISE4WMQ	Definitive	Autosomal dominant	[3]
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[1]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[6]
Cardiac failure	DISDC067	Strong	Biomarker	[7]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[8]
Chromosomal disorder	DISM5BB5	Strong	Altered Expression	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[10]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[7]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[11]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[11]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[12]
Fetal growth restriction	DIS5WEJ5	Strong	Biomarker	[13]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[14]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[15]
Intellectual disability	DISMBNXP	Strong	Biomarker	[13]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Altered Expression	[16]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[13]
Leukemia	DISNAKFL	Strong	Altered Expression	[17]
Lung cancer	DISCM4YA	Strong	Altered Expression	[18]
Lung carcinoma	DISTR26C	Strong	Biomarker	[18]
Mantle cell lymphoma	DISFREOV	Strong	Genetic Variation	[19]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[16]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Biomarker	[20]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[4]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[12]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[12]
Prostate cancer	DISF190Y	Strong	Altered Expression	[20]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[20]
Rauch-Steindl syndrome	DISED2G0	Strong	Autosomal dominant	[21]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[14]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[22]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[23]
Cervical cancer	DISFSHPF	moderate	Biomarker	[16]
Cervical carcinoma	DIST4S00	moderate	Biomarker	[16]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[24]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[25]
High blood pressure	DISY2OHH	moderate	Biomarker	[26]
Kidney cancer	DISBIPKM	moderate	Altered Expression	[24]
Neoplasm	DISZKGEW	moderate	Altered Expression	[23]
Renal carcinoma	DISER9XT	moderate	Altered Expression	[24]
Renal cell carcinoma	DISQZ2X8	moderate	Biomarker	[24]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[1]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Biomarker	[27]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[28]

19 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 Histone-lysine N-methyltransferase NSD2 (NSD2).	[29]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Histone-lysine N-methyltransferase NSD2 (NSD2).	[30]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Histone-lysine N-methyltransferase NSD2 (NSD2).	[31]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Histone-lysine N-methyltransferase NSD2 (NSD2).	[32]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Histone-lysine N-methyltransferase NSD2 (NSD2).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Histone-lysine N-methyltransferase NSD2 (NSD2).	[36]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Histone-lysine N-methyltransferase NSD2 (NSD2).	[37]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Histone-lysine N-methyltransferase NSD2 (NSD2).	[37]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Histone-lysine N-methyltransferase NSD2 (NSD2).	[38]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Histone-lysine N-methyltransferase NSD2 (NSD2).	[39]
Berberine	DMC5Q8X	Phase 4	Berberine decreases the expression of Histone-lysine N-methyltransferase NSD2 (NSD2).	[40]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Histone-lysine N-methyltransferase NSD2 (NSD2).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Histone-lysine N-methyltransferase NSD2 (NSD2).	[41]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Histone-lysine N-methyltransferase NSD2 (NSD2).	[42]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Histone-lysine N-methyltransferase NSD2 (NSD2).	[43]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Histone-lysine N-methyltransferase NSD2 (NSD2).	[44]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Histone-lysine N-methyltransferase NSD2 (NSD2).	[45]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of Histone-lysine N-methyltransferase NSD2 (NSD2).	[46]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of Histone-lysine N-methyltransferase NSD2 (NSD2).	[47]

4 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 Histone-lysine N-methyltransferase NSD2 (NSD2).	[34]
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Histone-lysine N-methyltransferase NSD2 (NSD2).	[35]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Histone-lysine N-methyltransferase NSD2 (NSD2).	[35]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Histone-lysine N-methyltransferase NSD2 (NSD2).	[35]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DZNep	DM0JXBK	Investigative	DZNep increases the degradation of Histone-lysine N-methyltransferase NSD2 (NSD2).	[48]

References

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