Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMVVA7F)

• DOT Name: Neurogenic locus notch homolog protein 3 (NOTCH3)
• Synonyms: Notch 3
• Gene Name: NOTCH3
• Related Disease:
  Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1
  Lateral meningocele syndrome
  Infantile myofibromatosis
  Pulmonary arterial hypertension
  Myofibromatosis, infantile, 2
• UniProt ID: NOTC3_HUMAN
• PDB ID: 4ZLP; 5CZV; 5CZX; 6WQU; 6XSW; 8OS0
• Pfam ID: PF00023 ; PF12796 ; PF13637 ; PF00008 ; PF07645 ; PF12661 ; PF06816 ; PF07684 ; PF00066
• Sequence:
  MGPGARGRRRRRRPMSPPPPPPPVRALPLLLLLAGPGAAAPPCLDGSPCANGGRCTQLPS
  REAACLCPPGWVGERCQLEDPCHSGPCAGRGVCQSSVVAGTARFSCRCPRGFRGPDCSLP
  DPCLSSPCAHGARCSVGPDGRFLCSCPPGYQGRSCRSDVDECRVGEPCRHGGTCLNTPGS
  FRCQCPAGYTGPLCENPAVPCAPSPCRNGGTCRQSGDLTYDCACLPGFEGQNCEVNVDDC
  PGHRCLNGGTCVDGVNTYNCQCPPEWTGQFCTEDVDECQLQPNACHNGGTCFNTLGGHSC
  VCVNGWTGESCSQNIDDCATAVCFHGATCHDRVASFYCACPMGKTGLLCHLDDACVSNPC
  HEDAICDTNPVNGRAICTCPPGFTGGACDQDVDECSIGANPCEHLGRCVNTQGSFLCQCG
  RGYTGPRCETDVNECLSGPCRNQATCLDRIGQFTCICMAGFTGTYCEVDIDECQSSPCVN
  GGVCKDRVNGFSCTCPSGFSGSTCQLDVDECASTPCRNGAKCVDQPDGYECRCAEGFEGT
  LCDRNVDDCSPDPCHHGRCVDGIASFSCACAPGYTGTRCESQVDECRSQPCRHGGKCLDL
  VDKYLCRCPSGTTGVNCEVNIDDCASNPCTFGVCRDGINRYDCVCQPGFTGPLCNVEINE
  CASSPCGEGGSCVDGENGFRCLCPPGSLPPLCLPPSHPCAHEPCSHGICYDAPGGFRCVC
  EPGWSGPRCSQSLARDACESQPCRAGGTCSSDGMGFHCTCPPGVQGRQCELLSPCTPNPC
  EHGGRCESAPGQLPVCSCPQGWQGPRCQQDVDECAGPAPCGPHGICTNLAGSFSCTCHGG
  YTGPSCDQDINDCDPNPCLNGGSCQDGVGSFSCSCLPGFAGPRCARDVDECLSNPCGPGT
  CTDHVASFTCTCPPGYGGFHCEQDLPDCSPSSCFNGGTCVDGVNSFSCLCRPGYTGAHCQ
  HEADPCLSRPCLHGGVCSAAHPGFRCTCLESFTGPQCQTLVDWCSRQPCQNGGRCVQTGA
  YCLCPPGWSGRLCDIRSLPCREAAAQIGVRLEQLCQAGGQCVDEDSSHYCVCPEGRTGSH
  CEQEVDPCLAQPCQHGGTCRGYMGGYMCECLPGYNGDNCEDDVDECASQPCQHGGSCIDL
  VARYLCSCPPGTLGVLCEINEDDCGPGPPLDSGPRCLHNGTCVDLVGGFRCTCPPGYTGL
  RCEADINECRSGACHAAHTRDCLQDPGGGFRCLCHAGFSGPRCQTVLSPCESQPCQHGGQ
  CRPSPGPGGGLTFTCHCAQPFWGPRCERVARSCRELQCPVGVPCQQTPRGPRCACPPGLS
  GPSCRSFPGSPPGASNASCAAAPCLHGGSCRPAPLAPFFRCACAQGWTGPRCEAPAAAPE
  VSEEPRCPRAACQAKRGDQRCDRECNSPGCGWDGGDCSLSVGDPWRQCEALQCWRLFNNS
  RCDPACSSPACLYDNFDCHAGGRERTCNPVYEKYCADHFADGRCDQGCNTEECGWDGLDC
  ASEVPALLARGVLVLTVLLPPEELLRSSADFLQRLSAILRTSLRFRLDAHGQAMVFPYHR
  PSPGSEPRARRELAPEVIGSVVMLEIDNRLCLQSPENDHCFPDAQSAADYLGALSAVERL
  DFPYPLRDVRGEPLEPPEPSVPLLPLLVAGAVLLLVILVLGVMVARRKREHSTLWFPEGF
  SLHKDVASGHKGRREPVGQDALGMKNMAKGESLMGEVATDWMDTECPEAKRLKVEEPGMG
  AEEAVDCRQWTQHHLVAADIRVAPAMALTPPQGDADADGMDVNVRGPDGFTPLMLASFCG
  GALEPMPTEEDEADDTSASIISDLICQGAQLGARTDRTGETALHLAARYARADAAKRLLD
  AGADTNAQDHSGRTPLHTAVTADAQGVFQILIRNRSTDLDARMADGSTALILAARLAVEG
  MVEELIASHADVNAVDELGKSALHWAAAVNNVEATLALLKNGANKDMQDSKEETPLFLAA
  REGSYEAAKLLLDHFANREITDHLDRLPRDVAQERLHQDIVRLLDQPSGPRSPPGPHGLG
  PLLCPPGAFLPGLKAAQSGSKKSRRPPGKAGLGPQGPRGRGKKLTLACPGPLADSSVTLS
  PVDSLDSPRPFGGPPASPGGFPLEGPYAAATATAVSLAQLGGPGRAGLGRQPPGGCVLSL
  GLLNPVAVPLDWARLPPPAPPGPSFLLPLAPGPQLLNPGTPVSPQERPPPYLAVPGHGEE
  YPAAGAHSSPPKARFLRVPSEHPYLTPSPESPEHWASPSPPSLSDWSESTPSPATATGAM
  ATTTGALPAQPLPLSVPSSLAQAQTQLGPQPEVTPKRQVLA
• Function: Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 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.
• Tissue Specificity: Ubiquitously expressed in fetal and adult tissues.
• KEGG Pathway:
  Endocrine resistance (hsa01522)
  Notch sig.ling pathway (hsa04330)
  Apelin sig.ling pathway (hsa04371)
  Th1 and Th2 cell differentiation (hsa04658)
  Thyroid hormone sig.ling pathway (hsa04919)
  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)
  Notch-HLH transcription pathway (R-HSA-350054)
  Defective LFNG causes SCDO3 (R-HSA-5083630)
  NOTCH3 Activation and Transmission of Signal to the Nucleus (R-HSA-9013507)
  NOTCH3 Intracellular Domain Regulates Transcription (R-HSA-9013508)
  Noncanonical activation of NOTCH3 (R-HSA-9017802)
  Pre-NOTCH Processing in the Endoplasmic Reticulum (R-HSA-1912399)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	DISNAJ8G	Definitive	Autosomal dominant	[1]
Lateral meningocele syndrome	DISG74RP	Strong	Autosomal dominant	[2]
Infantile myofibromatosis	DISXT8Z7	Supportive	Autosomal dominant	[3]
Pulmonary arterial hypertension	DISP8ZX5	Disputed	Autosomal dominant	[4]
Myofibromatosis, infantile, 2	DISGZ327	Limited	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Neurogenic locus notch homolog protein 3 (NOTCH3).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Neurogenic locus notch homolog protein 3 (NOTCH3).	[6]
Marinol	DM70IK5	Approved	Marinol increases the expression of Neurogenic locus notch homolog protein 3 (NOTCH3).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Neurogenic locus notch homolog protein 3 (NOTCH3).	[8]
Selenium	DM25CGV	Approved	Selenium increases the expression of Neurogenic locus notch homolog protein 3 (NOTCH3).	[9]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Neurogenic locus notch homolog protein 3 (NOTCH3).	[10]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Neurogenic locus notch homolog protein 3 (NOTCH3).	[11]
Tetracycline	DMZA017	Approved	Tetracycline decreases the expression of Neurogenic locus notch homolog protein 3 (NOTCH3).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Neurogenic locus notch homolog protein 3 (NOTCH3).	[14]
UNC0379	DMD1E4J	Preclinical	UNC0379 decreases the expression of Neurogenic locus notch homolog protein 3 (NOTCH3).	[15]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Neurogenic locus notch homolog protein 3 (NOTCH3).	[17]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Neurogenic locus notch homolog protein 3 (NOTCH3).	[18]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Neurogenic locus notch homolog protein 3 (NOTCH3).	[19]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of Neurogenic locus notch homolog protein 3 (NOTCH3).	[10]
N-dodecylgallate	DMV5RZM	Investigative	N-dodecylgallate increases the expression of Neurogenic locus notch homolog protein 3 (NOTCH3).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Neurogenic locus notch homolog protein 3 (NOTCH3).	[13]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Neurogenic locus notch homolog protein 3 (NOTCH3).	[16]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome. Am J Med Genet A. 2015 Feb;167A(2):271-81. doi: 10.1002/ajmg.a.36863. Epub 2014 Nov 13.
• [3] Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis. Am J Hum Genet. 2013 Jun 6;92(6):1001-7. doi: 10.1016/j.ajhg.2013.04.024. Epub 2013 May 23.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [8] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [9] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [10] Prediction of the contact sensitizing potential of chemicals using analysis of gene expression changes in human THP-1 monocytes. Toxicol Lett. 2010 Nov 10;199(1):51-9.
• [11] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [12] Effects of residual levels of tetracycline on the barrier functions of human intestinal epithelial cells. Food Chem Toxicol. 2017 Nov;109(Pt 1):253-263. doi: 10.1016/j.fct.2017.09.004. Epub 2017 Sep 4.
• [13] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [14] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [15] Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [17] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [18] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [19] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.