Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF6OOLU)

• DOT Name: Nipped-B-like protein (NIPBL)
• Synonyms: Delangin; SCC2 homolog
• Gene Name: NIPBL
• Related Disease:
  Cornelia de Lange syndrome
  Cornelia de Lange syndrome 1
  Anxiety
  Bone development disease
  Breast cancer
  Breast carcinoma
  Coffin-Siris syndrome
  Colonic neoplasm
  Colorectal neoplasm
  Congenital deformities of limbs
  Congenital diaphragmatic hernia
  Cornelia de Lange syndrome 2
  Cornelia de Lange syndrome 3
  Hearing disorder
  Hypopharyngeal carcinoma
  Intellectual disability
  Lung cancer
  Lung carcinoma
  Microcephaly
  Neoplasm
  Non-small-cell lung cancer
  Oropharyngeal squamous cell carcinoma
  Ptosis
  Roberts-SC phocomelia syndrome
  Sensorineural hearing loss disorder
  Thrombocytopenia
  Trichohepatoenteric syndrome
  Turner syndrome
  Wilms tumor
  Classic Hodgkin lymphoma
  Head-neck squamous cell carcinoma
  Rubinstein-Taybi syndrome
  Spinocerebellar ataxia 44
  Squamous cell carcinoma
  Advanced cancer
  Anxiety disorder
• UniProt ID: NIPBL_HUMAN
• PDB ID: 6WG3; 6WGE; 7W1M
• Pfam ID: PF12765 ; PF12830
• Sequence:
  MNGDMPHVPITTLAGIASLTDLLNQLPLPSPLPATTTKSLLFNARIAEEVNCLLACRDDN
  LVSQLVHSLNQVSTDHIELKDNLGSDDPEGDIPVLLQAVLARSPNVFREKSMQNRYVQSG
  MMMSQYKLSQNSMHSSPASSNYQQTTISHSPSSRFVPPQTSSGNRFMPQQNSPVPSPYAP
  QSPAGYMPYSHPSSYTTHPQMQQASVSSPIVAGGLRNIHDNKVSGPLSGNSANHHADNPR
  HGSSEDYLHMVHRLSSDDGDSSTMRNAASFPLRSPQPVCSPAGSEGTPKGSRPPLILQSQ
  SLPCSSPRDVPPDILLDSPERKQKKQKKMKLGKDEKEQSEKAAMYDIISSPSKDSTKLTL
  RLSRVRSSDMDQQEDMISGVENSNVSENDIPFNVQYPGQTSKTPITPQDINRPLNAAQCL
  SQQEQTAFLPANQVPVLQQNTSVAAKQPQTSVVQNQQQISQQGPIYDEVELDALAEIERI
  ERESAIERERFSKEVQDKDKPLKKRKQDSYPQEAGGATGGNRPASQETGSTGNGSRPALM
  VSIDLHQAGRVDSQASITQDSDSIKKPEEIKQCNDAPVSVLQEDIVGSLKSTPENHPETP
  KKKSDPELSKSEMKQSESRLAESKPNENRLVETKSSENKLETKVETQTEELKQNESRTTE
  CKQNESTIVEPKQNENRLSDTKPNDNKQNNGRSETTKSRPETPKQKGESRPETPKQKSDG
  HPETPKQKGDGRPETPKQKGESRPETPKQKNEGRPETPKHRHDNRRDSGKPSTEKKPEVS
  KHKQDTKSDSPRLKSERAEALKQRPDGRSVSESLRRDHDNKQKSDDRGESERHRGDQSRV
  RRPETLRSSSRNEHGIKSDSSKTDKLERKHRHESGDSRERPSSGEQKSRPDSPRVKQGDS
  NKSRSDKLGFKSPTSKDDKRTEGNKSKVDTNKAHPDNKAEFPSYLLGGRSGALKNFVIPK
  IKRDKDGNVTQETKKMEMKGEPKDKVEKIGLVEDLNKGAKPVVVLQKLSLDDVQKLIKDR
  EDKSRSSLKPIKNKPSKSNKGSIDQSVLKELPPELLAEIESTMPLCERVKMNKRKRSTVN
  EKPKYAEISSDEDNDSDEAFESSRKRHKKDDDKAWEYEERDRRSSGDHRRSGHSHEGRRS
  SGGGRYRNRSPSDSDMEDYSPPPSLSEVARKMKKKEKQKKRKAYEPKLTPEEMMDSSTFK
  RFTASIENILDNLEDMDFTAFGDDDEIPQELLLGKHQLNELGSESAKIKAMGIMDKLSTD
  KTVKVLNILEKNIQDGSKLSTLLNHNNDTEEEERLWRDLIMERVTKSADACLTTINIMTS
  PNMPKAVYIEDVIERVIQYTKFHLQNTLYPQYDPVYRLDPHGGGLLSSKAKRAKCSTHKQ
  RVIVMLYNKVCDIVSSLSELLEIQLLTDTTILQVSSMGITPFFVENVSELQLCAIKLVTA
  VFSRYEKHRQLILEEIFTSLARLPTSKRSLRNFRLNSSDMDGEPMYIQMVTALVLQLIQC
  VVHLPSSEKDSNAEEDSNKKIDQDVVITNSYETAMRTAQNFLSIFLKKCGSKQGEEDYRP
  LFENFVQDLLSTVNKPEWPAAELLLSLLGRLLVHQFSNKSTEMALRVASLDYLGTVAARL
  RKDAVTSKMDQGSIERILKQVSGGEDEIQQLQKALLDYLDENTETDPSLVFSRKFYIAQW
  FRDTTLETEKAMKSQKDEESSEGTHHAKEIETTGQIMHRAENRKKFLRSIIKTTPSQFST
  LKMNSDTVDYDDACLIVRYLASMRPFAQSFDIYLTQILRVLGENAIAVRTKAMKCLSEVV
  AVDPSILARLDMQRGVHGRLMDNSTSVREAAVELLGRFVLCRPQLAEQYYDMLIERILDT
  GISVRKRVIKILRDICIEQPTFPKITEMCVKMIRRVNDEEGIKKLVNETFQKLWFTPTPH
  NDKEAMTRKILNITDVVAACRDTGYDWFEQLLQNLLKSEEDSSYKPVKKACTQLVDNLVE
  HILKYEESLADSDNKGVNSGRLVACITTLFLFSKIRPQLMVKHAMTMQPYLTTKCSTQND
  FMVICNVAKILELVVPLMEHPSETFLATIEEDLMKLIIKYGMTVVQHCVSCLGAVVNKVT
  QNFKFVWACFNRYYGAISKLKSQHQEDPNNTSLLTNKPALLRSLFTVGALCRHFDFDLED
  FKGNSKVNIKDKVLELLMYFTKHSDEEVQTKAIIGLGFAFIQHPSLMFEQEVKNLYNNIL
  SDKNSSVNLKIQVLKNLQTYLQEEDTRMQQADRDWKKVAKQEDLKEMGDVSSGMSSSIMQ
  LYLKQVLEAFFHTQSSVRHFALNVIALTLNQGLIHPVQCVPYLIAMGTDPEPAMRNKADQ
  QLVEIDKKYAGFIHMKAVAGMKMSYQVQQAINTCLKDPVRGFRQDESSSALCSHLYSMIR
  GNRQHRRAFLISLLNLFDDTAKTDVTMLLYIADNLACFPYQTQEEPLFIMHHIDITLSVS
  GSNLLQSFKESMVKDKRKERKSSPSKENESSDSEEEVSRPRKSRKRVDSDSDSDSEDDIN
  SVMKCLPENSAPLIEFANVSQGILLLLMLKQHLKNLCGFSDSKIQKYSPSESAKVYDKAI
  NRKTGVHFHPKQTLDFLRSDMANSKITEEVKRSIVKQYLDFKLLMEHLDPDEEEEEGEVS
  ASTNARNKAITSLLGGGSPKNNTAAETEDDESDGEDRGGGTSGSLRRSKRNSDSTELAAQ
  MNESVDVMDVIAICCPKYKDRPQIARVVQKTSSGFSVQWMAGSYSGSWTEAKRRDGRKLV
  PWVDTIKESDIIYKKIALTSANKLTNKVVQTLRSLYAAKDGTSS
• Function: Plays an important role in the loading of the cohesin complex on to DNA. Forms a heterodimeric complex (also known as cohesin loading complex) with MAU2/SCC4 which mediates the loading of the cohesin complex onto chromatin. Plays a role in cohesin loading at sites of DNA damage. Its recruitment to double-strand breaks (DSBs) sites occurs in a CBX3-, RNF8- and RNF168-dependent manner whereas its recruitment to UV irradiation-induced DNA damage sites occurs in a ATM-, ATR-, RNF8- and RNF168-dependent manner. Along with ZNF609, promotes cortical neuron migration during brain development by regulating the transcription of crucial genes in this process. Preferentially binds promoters containing paused RNA polymerase II. Up-regulates the expression of SEMA3A, NRP1, PLXND1 and GABBR2 genes, among others.
• Tissue Specificity: Widely expressed. Highly expressed in heart, skeletal muscle, fetal and adult liver, fetal and adult kidney. Expressed at intermediates level in thymus, placenta, peripheral leukocyte and small intestine. Weakly or not expressed in brain, colon, spleen and lung.
• KEGG Pathway: Cell cycle (hsa04110)
• Reactome Pathway: Cohesin Loading onto Chromatin (R-HSA-2470946)

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cornelia de Lange syndrome	DISEQSXO	Definitive	Autosomal dominant	[1]
Cornelia de Lange syndrome 1	DIS1UHD6	Definitive	Autosomal dominant	[2]
Anxiety	DISIJDBA	Strong	Genetic Variation	[3]
Bone development disease	DISVKAZS	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Coffin-Siris syndrome	DIS8L03H	Strong	Genetic Variation	[6]
Colonic neoplasm	DISSZ04P	Strong	Genetic Variation	[7]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[8]
Congenital deformities of limbs	DISP4N1Q	Strong	Genetic Variation	[9]
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Genetic Variation	[10]
Cornelia de Lange syndrome 2	DISUCHUA	Strong	Biomarker	[11]
Cornelia de Lange syndrome 3	DIS69WC6	Strong	Biomarker	[11]
Hearing disorder	DIS4UTK4	Strong	Biomarker	[4]
Hypopharyngeal carcinoma	DISLOSB4	Strong	Biomarker	[12]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[13]
Lung cancer	DISCM4YA	Strong	Biomarker	[14]
Lung carcinoma	DISTR26C	Strong	Biomarker	[14]
Microcephaly	DIS2GRD8	Strong	CausalMutation	[15]
Neoplasm	DISZKGEW	Strong	Altered Expression	[14]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[14]
Oropharyngeal squamous cell carcinoma	DIS7D7QV	Strong	Biomarker	[16]
Ptosis	DISJZNIY	Strong	Biomarker	[17]
Roberts-SC phocomelia syndrome	DIS4JXZ4	Strong	Biomarker	[18]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[19]
Thrombocytopenia	DISU61YW	Strong	Genetic Variation	[20]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[21]
Turner syndrome	DIS2035C	Strong	Genetic Variation	[22]
Wilms tumor	DISB6T16	Strong	Genetic Variation	[23]
Classic Hodgkin lymphoma	DISV1LU6	moderate	Genetic Variation	[19]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Biomarker	[24]
Rubinstein-Taybi syndrome	DISVF1HM	moderate	Genetic Variation	[25]
Spinocerebellar ataxia 44	DISZ9ED6	moderate	Genetic Variation	[26]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[27]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[27]
Anxiety disorder	DISBI2BT	Limited	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	Nipped-B-like protein (NIPBL) affects the response to substance of Afimoxifene.	[40]

12 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 Nipped-B-like protein (NIPBL).	[28]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Nipped-B-like protein (NIPBL).	[29]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Nipped-B-like protein (NIPBL).	[30]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Nipped-B-like protein (NIPBL).	[32]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Nipped-B-like protein (NIPBL).	[33]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Nipped-B-like protein (NIPBL).	[34]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Nipped-B-like protein (NIPBL).	[35]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Nipped-B-like protein (NIPBL).	[36]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Nipped-B-like protein (NIPBL).	[33]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Nipped-B-like protein (NIPBL).	[37]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Nipped-B-like protein (NIPBL).	[38]
BRN-3548355	DM4KXT0	Investigative	BRN-3548355 increases the expression of Nipped-B-like protein (NIPBL).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin affects the phosphorylation of Nipped-B-like protein (NIPBL).	[31]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Nipped-B-like protein (NIPBL).	[31]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Nipped-B-like protein (NIPBL).	[31]

References

• [1] 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.
• [2] NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome. Nat Genet. 2004 Jun;36(6):636-41. doi: 10.1038/ng1363. Epub 2004 May 16.
• [3] Cornelia de Lange syndrome: a case study.Genet Test Mol Biomarkers. 2009 Feb;13(1):15-8. doi: 10.1089/gtmb.2008.0057.
• [4] Multiple organ system defects and transcriptional dysregulation in the Nipbl(+/-) mouse, a model of Cornelia de Lange Syndrome.PLoS Genet. 2009 Sep;5(9):e1000650. doi: 10.1371/journal.pgen.1000650. Epub 2009 Sep 18.
• [5] Downregulation of Cohesin Loading Factor Nipped-B-Like Protein (NIPBL) Induces Cell Cycle Arrest, Apoptosis, and Autophagy of Breast Cancer Cell Lines.Med Sci Monit. 2017 Oct 7;23:4817-4825. doi: 10.12659/msm.906583.
• [6] Mutations in chromatin regulators functionally link Cornelia de Lange syndrome and clinically overlapping phenotypes.Hum Genet. 2017 Mar;136(3):307-320. doi: 10.1007/s00439-017-1758-y. Epub 2017 Jan 24.
• [7] Genome-wide association and fine mapping of genetic loci predisposing to colon carcinogenesis in mice.Mol Cancer Res. 2012 Jan;10(1):66-74. doi: 10.1158/1541-7786.MCR-10-0540. Epub 2011 Nov 29.
• [8] Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers.Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3443-8. doi: 10.1073/pnas.0712384105. Epub 2008 Feb 25.
• [9] Molecular confirmation of nine cases of Cornelia de Lange syndrome diagnosed prenatally.Prenat Diagn. 2014 Feb;34(2):163-7. doi: 10.1002/pd.4279. Epub 2013 Dec 9.
• [10] Brachmann-de Lange syndrome with congenital diaphragmatic hernia and NIPBL gene mutation.Congenit Anom (Kyoto). 2010 Jun;50(2):129-32. doi: 10.1111/j.1741-4520.2010.00270.x. Epub 2010 Feb 11.
• [11] BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange-like syndrome. Nat Genet. 2018 Mar;50(3):329-332. doi: 10.1038/s41588-018-0042-y. Epub 2018 Jan 29.
• [12] HSV-1 Infection Modulates the Radioresponse of a HPV16-positive Head and Neck Cancer Cell Line.Anticancer Res. 2016 Feb;36(2):565-74.
• [13] Nipbl Interacts with Zfp609 and the Integrator Complex to Regulate Cortical Neuron Migration.Neuron. 2017 Jan 18;93(2):348-361. doi: 10.1016/j.neuron.2016.11.047. Epub 2016 Dec 29.
• [14] Inhibition of NIPBL enhances the chemosensitivity of non-small-cell lung cancer cells via the DNA damage response and autophagy pathway.Onco Targets Ther. 2018 Apr 5;11:1941-1948. doi: 10.2147/OTT.S158655. eCollection 2018.
• [15] A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders.Genet Med. 2016 Nov;18(11):1090-1096. doi: 10.1038/gim.2016.1. Epub 2016 Mar 3.
• [16] Extracellular vesicle microRNA cargo is correlated with HPV status in oropharyngeal carcinoma.J Oral Pathol Med. 2018 Nov;47(10):954-963. doi: 10.1111/jop.12781. Epub 2018 Oct 10.
• [17] Ophthalmologic findings in Cornelia de Lange syndrome: a genotype-phenotype correlation study.Arch Ophthalmol. 2006 Apr;124(4):552-7. doi: 10.1001/archopht.124.4.552.
• [18] Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation. Am J Hum Genet. 2007 Mar;80(3):485-94. doi: 10.1086/511888. Epub 2007 Jan 17.
• [19] Audiological findings, genotype and clinical severity score in Cornelia de Lange syndrome.Int J Pediatr Otorhinolaryngol. 2014 Jul;78(7):1045-8. doi: 10.1016/j.ijporl.2014.03.038. Epub 2014 Apr 8.
• [20] Genomic organisation of the human chordin gene and mutation screening of candidate Cornelia de Lange syndrome genes.Hum Genet. 1999 Jul-Aug;105(1-2):104-11. doi: 10.1007/s004399900068.
• [21] Novel mosaic variants in two patients with Cornelia de Lange syndrome.Eur J Med Genet. 2018 Nov;61(11):680-684. doi: 10.1016/j.ejmg.2017.11.004. Epub 2017 Nov 15.
• [22] Special cases in Cornelia de Lange syndrome: The Spanish experience.Am J Med Genet C Semin Med Genet. 2016 Jun;172(2):198-205. doi: 10.1002/ajmg.c.31501. Epub 2016 May 10.
• [23] Unusual association of non-anaplastic Wilms tumor and Cornelia de Lange syndrome: case report.BMC Cancer. 2016 Jun 13;16:365. doi: 10.1186/s12885-016-2402-2.
• [24] Methyl-donor depletion of head and neck cancer cells in vitro establishes a less aggressive tumour cell phenotype.Eur J Nutr. 2018 Jun;57(4):1321-1332. doi: 10.1007/s00394-017-1411-5. Epub 2017 Mar 1.
• [25] Next generation sequencing identified two novel mutations in NIPBL and a frame shift mutation in CREBBP in three Chinese children.Orphanet J Rare Dis. 2019 Feb 15;14(1):45. doi: 10.1186/s13023-019-1022-8.
• [26] Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes.Psychiatry Clin Neurosci. 2019 Jan;73(1):11-19. doi: 10.1111/pcn.12788. Epub 2018 Dec 12.
• [27] Two different protein expression profiles of oral squamous cell carcinoma analyzed by immunoprecipitation high-performance liquid chromatography.World J Surg Oncol. 2017 Aug 8;15(1):151. doi: 10.1186/s12957-017-1213-5.
• [28] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [29] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [30] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [31] 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.
• [32] 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.
• [33] 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.
• [34] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [35] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [36] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [37] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [38] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [39] Circular RNA circNIPBL promotes NNK-induced DNA damage in bronchial epithelial cells via the base excision repair pathway. Arch Toxicol. 2022 Jul;96(7):2049-2065. doi: 10.1007/s00204-022-03297-z. Epub 2022 Apr 18.
• [40] Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen. Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2730-5. doi: 10.1073/pnas.1018872108. Epub 2011 Apr 11.