Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ3Y9PA)

• DOT Name: Neurogenic locus notch homolog protein 2 (NOTCH2)
• Synonyms: Notch 2; hN2
• Gene Name: NOTCH2
• Related Disease:
  Acroosteolysis dominant type
  Alagille syndrome due to a NOTCH2 point mutation
  Alagille syndrome
• UniProt ID: NOTC2_HUMAN
• PDB ID: 2OO4; 5MWB
• Pfam ID: PF00023 ; PF12796 ; PF00008 ; PF07645 ; PF12661 ; PF06816 ; PF07684 ; PF00066
• Sequence:
  MPALRPALLWALLALWLCCAAPAHALQCRDGYEPCVNEGMCVTYHNGTGYCKCPEGFLGE
  YCQHRDPCEKNRCQNGGTCVAQAMLGKATCRCASGFTGEDCQYSTSHPCFVSRPCLNGGT
  CHMLSRDTYECTCQVGFTGKECQWTDACLSHPCANGSTCTTVANQFSCKCLTGFTGQKCE
  TDVNECDIPGHCQHGGTCLNLPGSYQCQCPQGFTGQYCDSLYVPCAPSPCVNGGTCRQTG
  DFTFECNCLPGFEGSTCERNIDDCPNHRCQNGGVCVDGVNTYNCRCPPQWTGQFCTEDVD
  ECLLQPNACQNGGTCANRNGGYGCVCVNGWSGDDCSENIDDCAFASCTPGSTCIDRVASF
  SCMCPEGKAGLLCHLDDACISNPCHKGALCDTNPLNGQYICTCPQGYKGADCTEDVDECA
  MANSNPCEHAGKCVNTDGAFHCECLKGYAGPRCEMDINECHSDPCQNDATCLDKIGGFTC
  LCMPGFKGVHCELEINECQSNPCVNNGQCVDKVNRFQCLCPPGFTGPVCQIDIDDCSSTP
  CLNGAKCIDHPNGYECQCATGFTGVLCEENIDNCDPDPCHHGQCQDGIDSYTCICNPGYM
  GAICSDQIDECYSSPCLNDGRCIDLVNGYQCNCQPGTSGVNCEINFDDCASNPCIHGICM
  DGINRYSCVCSPGFTGQRCNIDIDECASNPCRKGATCINGVNGFRCICPEGPHHPSCYSQ
  VNECLSNPCIHGNCTGGLSGYKCLCDAGWVGINCEVDKNECLSNPCQNGGTCDNLVNGYR
  CTCKKGFKGYNCQVNIDECASNPCLNQGTCFDDISGYTCHCVLPYTGKNCQTVLAPCSPN
  PCENAAVCKESPNFESYTCLCAPGWQGQRCTIDIDECISKPCMNHGLCHNTQGSYMCECP
  PGFSGMDCEEDIDDCLANPCQNGGSCMDGVNTFSCLCLPGFTGDKCQTDMNECLSEPCKN
  GGTCSDYVNSYTCKCQAGFDGVHCENNINECTESSCFNGGTCVDGINSFSCLCPVGFTGS
  FCLHEINECSSHPCLNEGTCVDGLGTYRCSCPLGYTGKNCQTLVNLCSRSPCKNKGTCVQ
  KKAESQCLCPSGWAGAYCDVPNVSCDIAASRRGVLVEHLCQHSGVCINAGNTHYCQCPLG
  YTGSYCEEQLDECASNPCQHGATCSDFIGGYRCECVPGYQGVNCEYEVDECQNQPCQNGG
  TCIDLVNHFKCSCPPGTRGLLCEENIDDCARGPHCLNGGQCMDRIGGYSCRCLPGFAGER
  CEGDINECLSNPCSSEGSLDCIQLTNDYLCVCRSAFTGRHCETFVDVCPQMPCLNGGTCA
  VASNMPDGFICRCPPGFSGARCQSSCGQVKCRKGEQCVHTASGPRCFCPSPRDCESGCAS
  SPCQHGGSCHPQRQPPYYSCQCAPPFSGSRCELYTAPPSTPPATCLSQYCADKARDGVCD
  EACNSHACQWDGGDCSLTMENPWANCSSPLPCWDYINNQCDELCNTVECLFDNFECQGNS
  KTCKYDKYCADHFKDNHCDQGCNSEECGWDGLDCAADQPENLAEGTLVIVVLMPPEQLLQ
  DARSFLRALGTLLHTNLRIKRDSQGELMVYPYYGEKSAAMKKQRMTRRSLPGEQEQEVAG
  SKVFLEIDNRQCVQDSDHCFKNTDAAAALLASHAIQGTLSYPLVSVVSESLTPERTQLLY
  LLAVAVVIILFIILLGVIMAKRKRKHGSLWLPEGFTLRRDASNHKRREPVGQDAVGLKNL
  SVQVSEANLIGTGTSEHWVDDEGPQPKKVKAEDEALLSEEDDPIDRRPWTQQHLEAADIR
  RTPSLALTPPQAEQEVDVLDVNVRGPDGCTPLMLASLRGGSSDLSDEDEDAEDSSANIIT
  DLVYQGASLQAQTDRTGEMALHLAARYSRADAAKRLLDAGADANAQDNMGRCPLHAAVAA
  DAQGVFQILIRNRVTDLDARMNDGTTPLILAARLAVEGMVAELINCQADVNAVDDHGKSA
  LHWAAAVNNVEATLLLLKNGANRDMQDNKEETPLFLAAREGSYEAAKILLDHFANRDITD
  HMDRLPRDVARDRMHHDIVRLLDEYNVTPSPPGTVLTSALSPVICGPNRSFLSLKHTPMG
  KKSRRPSAKSTMPTSLPNLAKEAKDAKGSRRKKSLSEKVQLSESSVTLSPVDSLESPHTY
  VSDTTSSPMITSPGILQASPNPMLATAAPPAPVHAQHALSFSNLHEMQPLAHGASTVLPS
  VSQLLSHHHIVSPGSGSAGSLSRLHPVPVPADWMNRMEVNETQYNEMFGMVLAPAEGTHP
  GIAPQSRPPEGKHITTPREPLPPIVTFQLIPKGSIAQPAGAPQPQSTCPPAVAGPLPTMY
  QIPEMARLPSVAFPTAMMPQQDGQVAQTILPAYHPFPASVGKYPTPPSQHSYASSNAAER
  TPSHSGHLQGEHPYLTPSPESPDQWSSSSPHSASDWSDVTTSPTPGGAGGGQRGPGTHMS
  EPPHNNMQVYA
• 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 bone remodeling and homeostasis. In collaboration with RELA/p65 enhances NFATc1 promoter activity and positively regulates RANKL-induced osteoclast differentiation. Positively regulates self-renewal of liver cancer cells.
• Tissue Specificity: Expressed in the brain, heart, kidney, lung, skeletal muscle and liver. Ubiquitously expressed in the embryo.
• KEGG Pathway:
  Endocrine resistance (hsa01522)
  Notch sig.ling pathway (hsa04330)
  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)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Breast cancer (hsa05224)
• Reactome Pathway:
  Pre-NOTCH Transcription and Translation (R-HSA-1912408)
  Pre-NOTCH Processing in Golgi (R-HSA-1912420)
  NOTCH2 intracellular domain regulates transcription (R-HSA-2197563)
  NOTCH2 Activation and Transmission of Signal to the Nucleus (R-HSA-2979096)
  Notch-HLH transcription pathway (R-HSA-350054)
  Defective LFNG causes SCDO3 (R-HSA-5083630)
  NOTCH4 Intracellular Domain Regulates Transcription (R-HSA-9013695)
  Pre-NOTCH Processing in the Endoplasmic Reticulum (R-HSA-1912399)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acroosteolysis dominant type	DISL732V	Definitive	Autosomal dominant	[1]
Alagille syndrome due to a NOTCH2 point mutation	DISZGPUX	Strong	Autosomal dominant	[2]
Alagille syndrome	DIS9DPU8	Moderate	Autosomal dominant	[3]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Neurogenic locus notch homolog protein 2 (NOTCH2) affects the response to substance of Cisplatin.	[25]
Arsenic	DMTL2Y1	Approved	Neurogenic locus notch homolog protein 2 (NOTCH2) affects the response to substance of Arsenic.	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Neurogenic locus notch homolog protein 2 (NOTCH2).	[4]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Neurogenic locus notch homolog protein 2 (NOTCH2).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Neurogenic locus notch homolog protein 2 (NOTCH2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Neurogenic locus notch homolog protein 2 (NOTCH2).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Neurogenic locus notch homolog protein 2 (NOTCH2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Neurogenic locus notch homolog protein 2 (NOTCH2).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Neurogenic locus notch homolog protein 2 (NOTCH2).	[9]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Neurogenic locus notch homolog protein 2 (NOTCH2).	[10]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Neurogenic locus notch homolog protein 2 (NOTCH2).	[11]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Neurogenic locus notch homolog protein 2 (NOTCH2).	[12]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Neurogenic locus notch homolog protein 2 (NOTCH2).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Neurogenic locus notch homolog protein 2 (NOTCH2).	[14]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Neurogenic locus notch homolog protein 2 (NOTCH2).	[15]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Neurogenic locus notch homolog protein 2 (NOTCH2).	[16]
PEITC	DMOMN31	Phase 2	PEITC increases the expression of Neurogenic locus notch homolog protein 2 (NOTCH2).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Neurogenic locus notch homolog protein 2 (NOTCH2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Neurogenic locus notch homolog protein 2 (NOTCH2).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Neurogenic locus notch homolog protein 2 (NOTCH2).	[20]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Neurogenic locus notch homolog protein 2 (NOTCH2).	[22]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Neurogenic locus notch homolog protein 2 (NOTCH2).	[23]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Neurogenic locus notch homolog protein 2 (NOTCH2).	[24]

References

• [1] Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat Genet. 2011 Mar 6;43(4):306-8. doi: 10.1038/ng.778.
• [2] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet. 2006 Jul;79(1):169-73. doi: 10.1086/505332. Epub 2006 May 10.
• [4] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [5] Differential responses to retinoic acid and endocrine disruptor compounds of subpopulations within human embryonic stem cell lines. Differentiation. 2012 Nov;84(4):330-43. doi: 10.1016/j.diff.2012.07.006. Epub 2012 Aug 18.
• [6] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [8] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [11] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [12] Toxicoproteomics reveals an effect of clozapine on autophagy in human liver spheroids. Toxicol Mech Methods. 2023 Jun;33(5):401-410. doi: 10.1080/15376516.2022.2156005. Epub 2022 Dec 19.
• [13] 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.
• [14] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [15] Biological significance and therapeutic implication of resveratrol-inhibited Wnt, Notch and STAT3 signaling in cervical cancer cells. Genes Cancer. 2014 May;5(5-6):154-64. doi: 10.18632/genesandcancer.15.
• [16] Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1839-44. doi: 10.1073/pnas.1424171112. Epub 2015 Jan 20.
• [17] Notch activation by phenethyl isothiocyanate attenuates its inhibitory effect on prostate cancer cell migration. PLoS One. 2011;6(10):e26615. doi: 10.1371/journal.pone.0026615. Epub 2011 Oct 24.
• [18] Benzo[a]pyrene promotes proliferation of human lung cancer cells by accelerating the epidermal growth factor receptor signaling pathway. Cancer Lett. 2009 Jun 8;278(1):27-33. doi: 10.1016/j.canlet.2008.12.017. Epub 2009 Jan 31.
• [19] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] 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.
• [22] 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.
• [23] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.
• [24] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [25] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [26] Genetic susceptible locus in NOTCH2 interacts with arsenic in drinking water on risk of type 2 diabetes. PLoS One. 2013 Aug 14;8(8):e70792. doi: 10.1371/journal.pone.0070792. eCollection 2013.