Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI1WADQ)

• DOT Name: Neurogenic locus notch homolog protein 1 (NOTCH1)
• Synonyms: Notch 1; hN1; Translocation-associated notch protein TAN-1
• Gene Name: NOTCH1
• Related Disease:
  Adams-Oliver syndrome
  Adams-Oliver syndrome 5
  Aortic valve disease 1
  Connective tissue disorder
  Familial bicuspid aortic valve
  Familial thoracic aortic aneurysm and aortic dissection
• UniProt ID: NOTC1_HUMAN
• PDB ID: 1PB5; 1TOZ; 1YYH; 2F8X; 2F8Y; 2HE0; 2VJ3; 3ETO; 3I08; 3L95; 3NBN; 3V79; 4CUD; 4CUE; 4CUF; 4D0E; 4D0F; 5FM9; 5FMA; 5KZO; 5L0R; 5UB5; 6IDF; 6PY8; 8OR5; 8ORY; 8ORZ
• Pfam ID: PF00023 ; PF12796 ; PF13637 ; PF00008 ; PF07645 ; PF12661 ; PF06816 ; PF07684 ; PF00066
• Sequence:
  MPPLLAPLLCLALLPALAARGPRCSQPGETCLNGGKCEAANGTEACVCGGAFVGPRCQDP
  NPCLSTPCKNAGTCHVVDRRGVADYACSCALGFSGPLCLTPLDNACLTNPCRNGGTCDLL
  TLTEYKCRCPPGWSGKSCQQADPCASNPCANGGQCLPFEASYICHCPPSFHGPTCRQDVN
  ECGQKPGLCRHGGTCHNEVGSYRCVCRATHTGPNCERPYVPCSPSPCQNGGTCRPTGDVT
  HECACLPGFTGQNCEENIDDCPGNNCKNGGACVDGVNTYNCRCPPEWTGQYCTEDVDECQ
  LMPNACQNGGTCHNTHGGYNCVCVNGWTGEDCSENIDDCASAACFHGATCHDRVASFYCE
  CPHGRTGLLCHLNDACISNPCNEGSNCDTNPVNGKAICTCPSGYTGPACSQDVDECSLGA
  NPCEHAGKCINTLGSFECQCLQGYTGPRCEIDVNECVSNPCQNDATCLDQIGEFQCICMP
  GYEGVHCEVNTDECASSPCLHNGRCLDKINEFQCECPTGFTGHLCQYDVDECASTPCKNG
  AKCLDGPNTYTCVCTEGYTGTHCEVDIDECDPDPCHYGSCKDGVATFTCLCRPGYTGHHC
  ETNINECSSQPCRHGGTCQDRDNAYLCFCLKGTTGPNCEINLDDCASSPCDSGTCLDKID
  GYECACEPGYTGSMCNINIDECAGNPCHNGGTCEDGINGFTCRCPEGYHDPTCLSEVNEC
  NSNPCVHGACRDSLNGYKCDCDPGWSGTNCDINNNECESNPCVNGGTCKDMTSGYVCTCR
  EGFSGPNCQTNINECASNPCLNQGTCIDDVAGYKCNCLLPYTGATCEVVLAPCAPSPCRN
  GGECRQSEDYESFSCVCPTGWQGQTCEVDINECVLSPCRHGASCQNTHGGYRCHCQAGYS
  GRNCETDIDDCRPNPCHNGGSCTDGINTAFCDCLPGFRGTFCEEDINECASDPCRNGANC
  TDCVDSYTCTCPAGFSGIHCENNTPDCTESSCFNGGTCVDGINSFTCLCPPGFTGSYCQH
  DVNECDSQPCLHGGTCQDGCGSYRCTCPQGYTGPNCQNLVHWCDSSPCKNGGKCWQTHTQ
  YRCECPSGWTGLYCDVPSVSCEVAAQRQGVDVARLCQHGGLCVDAGNTHHCRCQAGYTGS
  YCEDLVDECSPSPCQNGATCTDYLGGYSCKCVAGYHGVNCSEEIDECLSHPCQNGGTCLD
  LPNTYKCSCPRGTQGVHCEINVDDCNPPVDPVSRSPKCFNNGTCVDQVGGYSCTCPPGFV
  GERCEGDVNECLSNPCDARGTQNCVQRVNDFHCECRAGHTGRRCESVINGCKGKPCKNGG
  TCAVASNTARGFICKCPAGFEGATCENDARTCGSLRCLNGGTCISGPRSPTCLCLGPFTG
  PECQFPASSPCLGGNPCYNQGTCEPTSESPFYRCLCPAKFNGLLCHILDYSFGGGAGRDI
  PPPLIEEACELPECQEDAGNKVCSLQCNNHACGWDGGDCSLNFNDPWKNCTQSLQCWKYF
  SDGHCDSQCNSAGCLFDGFDCQRAEGQCNPLYDQYCKDHFSDGHCDQGCNSAECEWDGLD
  CAEHVPERLAAGTLVVVVLMPPEQLRNSSFHFLRELSRVLHTNVVFKRDAHGQQMIFPYY
  GREEELRKHPIKRAAEGWAAPDALLGQVKASLLPGGSEGGRRRRELDPMDVRGSIVYLEI
  DNRQCVQASSQCFQSATDVAAFLGALASLGSLNIPYKIEAVQSETVEPPPPAQLHFMYVA
  AAAFVLLFFVGCGVLLSRKRRRQHGQLWFPEGFKVSEASKKKRREPLGEDSVGLKPLKNA
  SDGALMDDNQNEWGDEDLETKKFRFEEPVVLPDLDDQTDHRQWTQQHLDAADLRMSAMAP
  TPPQGEVDADCMDVNVRGPDGFTPLMIASCSGGGLETGNSEEEEDAPAVISDFIYQGASL
  HNQTDRTGETALHLAARYSRSDAAKRLLEASADANIQDNMGRTPLHAAVSADAQGVFQIL
  IRNRATDLDARMHDGTTPLILAARLAVEGMLEDLINSHADVNAVDDLGKSALHWAAAVNN
  VDAAVVLLKNGANKDMQNNREETPLFLAAREGSYETAKVLLDHFANRDITDHMDRLPRDI
  AQERMHHDIVRLLDEYNLVRSPQLHGAPLGGTPTLSPPLCSPNGYLGSLKPGVQGKKVRK
  PSSKGLACGSKEAKDLKARRKKSQDGKGCLLDSSGMLSPVDSLESPHGYLSDVASPPLLP
  SPFQQSPSVPLNHLPGMPDTHLGIGHLNVAAKPEMAALGGGGRLAFETGPPRLSHLPVAS
  GTSTVLGSSSGGALNFTVGGSTSLNGQCEWLSRLQSGMVPNQYNPLRGSVAPGPLSTQAP
  SLQHGMVGPLHSSLAASALSQMMSYQGLPSTRLATQPHLVQTQQVQPQNLQMQQQNLQPA
  NIQQQQSLQPPPPPPQPHLGVSSAASGHLGRSFLSGEPSQADVQPLGPSSLAVHTILPQE
  SPALPTSLPSSLVPPVTAAQFLTPPSQHSYSSPVDNTPSHQLQVPEHPFLTPSPESPDQW
  SSSSPHSNVSDWSEGVSSPPTSMQSQIARIPEAFK
• Function: Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting. Involved in the maturation of both CD4(+) and CD8(+) cells in the thymus. Important for follicular differentiation and possibly cell fate selection within the follicle. During cerebellar development, functions as a receptor for neuronal DNER and is involved in the differentiation of Bergmann glia. Represses neuronal and myogenic differentiation. May play an essential role in postimplantation development, probably in some aspect of cell specification and/or differentiation. May be involved in mesoderm development, somite formation and neurogenesis. May enhance HIF1A function by sequestering HIF1AN away from HIF1A. Required for the THBS4 function in regulating protective astrogenesis from the subventricular zone (SVZ) niche after injury. Involved in determination of left/right symmetry by modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO).
• Tissue Specificity: In fetal tissues most abundant in spleen, brain stem and lung. Also present in most adult tissues where it is found mainly in lymphoid tissues.
• KEGG Pathway:
  Endocrine resistance (hsa01522)
  Notch sig.ling pathway (hsa04330)
  Th1 and Th2 cell differentiation (hsa04658)
  Thyroid hormone sig.ling pathway (hsa04919)
  Prion disease (hsa05020)
  Human papillomavirus infection (hsa05165)
  Pathways in cancer (hsa05200)
  MicroR.s in cancer (hsa05206)
  Breast cancer (hsa05224)
• Reactome Pathway:
  Pre-NOTCH Transcription and Translation (R-HSA-1912408)
  Pre-NOTCH Processing in Golgi (R-HSA-1912420)
  Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells (R-HSA-210744)
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)
  Activated NOTCH1 Transmits Signal to the Nucleus (R-HSA-2122948)
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling (R-HSA-2644607)
  Constitutive Signaling by NOTCH1 t(7 (R-HSA-2660826)
  Constitutive Signaling by NOTCH1 HD Domain Mutants (R-HSA-2691232)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  Notch-HLH transcription pathway (R-HSA-350054)
  Defective LFNG causes SCDO3 (R-HSA-5083630)
  RUNX3 regulates NOTCH signaling (R-HSA-8941856)
  NOTCH3 Intracellular Domain Regulates Transcription (R-HSA-9013508)
  NOTCH4 Intracellular Domain Regulates Transcription (R-HSA-9013695)
  Formation of paraxial mesoderm (R-HSA-9793380)
  NFE2L2 regulating tumorigenic genes (R-HSA-9818030)
  Regulation of NFE2L2 gene expression (R-HSA-9818749)
  Somitogenesis (R-HSA-9824272)
  M1580_K2555) Translocation Mutant (9)(NOTCH1)
  Pre-NOTCH Processing in the Endoplasmic Reticulum (R-HSA-1912399)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adams-Oliver syndrome	DISQO525	Definitive	Autosomal dominant	[1]
Adams-Oliver syndrome 5	DISDRQHE	Definitive	Autosomal dominant	[2]
Aortic valve disease 1	DIS3JI56	Strong	Autosomal dominant	[3]
Connective tissue disorder	DISKXBS3	Moderate	Autosomal dominant	[2]
Familial bicuspid aortic valve	DISL0BRK	Supportive	Autosomal dominant	[1]
Familial thoracic aortic aneurysm and aortic dissection	DIS069FB	Limited	Autosomal dominant	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Neurogenic locus notch homolog protein 1 (NOTCH1) decreases the response to substance of Paclitaxel.	[48]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Neurogenic locus notch homolog protein 1 (NOTCH1).	[5]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the acetylation of Neurogenic locus notch homolog protein 1 (NOTCH1).	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[13]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the activity of Neurogenic locus notch homolog protein 1 (NOTCH1).	[14]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[15]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea decreases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[16]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[17]
Mebendazole	DMO14SG	Approved	Mebendazole decreases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[18]
Mitotane	DMU1GX0	Approved	Mitotane increases the activity of Neurogenic locus notch homolog protein 1 (NOTCH1).	[19]
Propranolol	DM79NTF	Approved	Propranolol decreases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[20]
Omacetaxine mepesuccinate	DMPU2WX	Approved	Omacetaxine mepesuccinate increases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[21]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[22]
Isoflavone	DM7U58J	Phase 4	Isoflavone decreases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[23]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[24]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[25]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[26]
Triptolide	DMCMDVR	Phase 3	Triptolide decreases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[27]
Glycyrrhizin	DM8M2N3	Phase 3	Glycyrrhizin decreases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[28]
PEITC	DMOMN31	Phase 2	PEITC increases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[29]
BAICALEIN	DM4C7E6	Phase 2	BAICALEIN increases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[31]
Eugenol	DM7US1H	Patented	Eugenol decreases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[32]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[33]
UNC0379	DMD1E4J	Preclinical	UNC0379 increases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[34]
Baicalin	DMY1TLZ	Terminated	Baicalin increases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[35]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[36]
Paraquat	DMR8O3X	Investigative	Paraquat affects the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[38]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[39]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[40]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[41]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[42]
U0126	DM31OGF	Investigative	U0126 increases the activity of Neurogenic locus notch homolog protein 1 (NOTCH1).	[43]
CATECHIN	DMY38SB	Investigative	CATECHIN increases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[44]
Tyrphostin Ag-1478	DM87ZIH	Investigative	Tyrphostin Ag-1478 increases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[45]
aconitine	DMFOZ60	Investigative	aconitine increases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[46]
ZM-447439	DMFP8WE	Investigative	ZM-447439 increases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[16]
Ro5203280	DM42UK5	Investigative	Ro5203280 increases the expression of Neurogenic locus notch homolog protein 1 (NOTCH1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the cleavage of Neurogenic locus notch homolog protein 1 (NOTCH1).	[12]
CYCLOPAMINE	DMEM2SW	Investigative	CYCLOPAMINE decreases the cleavage of Neurogenic locus notch homolog protein 1 (NOTCH1).	[47]

References

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• [36] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [37] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
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• [47] Effects of combination of notch inhibitor plus hedgehog inhibitor or Wnt inhibitor on growth of leukemia cells. Anticancer Res. 2011 Mar;31(3):893-6.
• [48] Inhibition of the notch signaling pathway overcomes resistance of cervical cancer cells to paclitaxel through retardation of the epithelial-mesenchymal transition process. Environ Toxicol. 2021 Sep;36(9):1758-1764. doi: 10.1002/tox.23296. Epub 2021 May 28.