Details of Drug Off-Target (DOT)

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

• DOT Name: Nck-associated protein 1 (NCKAP1)
• Synonyms: NAP 1; Membrane-associated protein HEM-2; p125Nap1
• Gene Name: NCKAP1
• Related Disease:
  Complex neurodevelopmental disorder
  Neurodevelopmental disorder
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Hypophosphatemia
  Non-small-cell lung cancer
  Psoriasis
  Thiel-Behnke corneal dystrophy
  Advanced cancer
  Hepatocellular carcinoma
  Neoplasm
  Neuroblastoma
• UniProt ID: NCKP1_HUMAN
• PDB ID: 3P8C; 4N78; 7USC; 7USD; 7USE
• Pfam ID: PF09735
• Sequence:
  MSRSVLQPSQQKLAEKLTILNDRGVGMLTRLYNIKKACGDPKAKPSYLIDKNLESAVKFI
  VRKFPAVETRNNNQQLAQLQKEKSEILKNLALYYFTFVDVMEFKDHVCELLNTIDVCQVF
  FDITVNFDLTKNYLDLIITYTTLMILLSRIEERKAIIGLYNYAHEMTHGASDREYPRLGQ
  MIVDYENPLKKMMEEFVPHSKSLSDALISLQMVYPRRNLSADQWRNAQLLSLISAPSTML
  NPAQSDTMPCEYLSLDAMEKWIIFGFILCHGILNTDATALNLWKLALQSSSCLSLFRDEV
  FHIHKAAEDLFVNIRGYNKRINDIRECKEAAVSHAGSMHRERRKFLRSALKELATVLSDQ
  PGLLGPKALFVFMALSFARDEIIWLLRHADNMPKKSADDFIDKHIAELIFYMEELRAHVR
  KYGPVMQRYYVQYLSGFDAVVLNELVQNLSVCPEDESIIMSSFVNTMTSLSVKQVEDGEV
  FDFRGMRLDWFRLQAYTSVSKASLGLADHRELGKMMNTIIFHTKMVDSLVEMLVETSDLS
  IFCFYSRAFEKMFQQCLELPSQSRYSIAFPLLCTHFMSCTHELCPEERHHIGDRSLSLCN
  MFLDEMAKQARNLITDICTEQCTLSDQLLPKHCAKTISQAVNKKSKKQTGKKGEPEREKP
  GVESMRKNRLVVTNLDKLHTALSELCFSINYVPNMVVWEHTFTPREYLTSHLEIRFTKSI
  VGMTMYNQATQEIAKPSELLTSVRAYMTVLQSIENYVQIDITRVFNNVLLQQTQHLDSHG
  EPTITSLYTNWYLETLLRQVSNGHIAYFPAMKAFVNLPTENELTFNAEEYSDISEMRSLS
  ELLGPYGMKFLSESLMWHISSQVAELKKLVVENVDVLTQMRTSFDKPDQMAALFKRLSSV
  DSVLKRMTIIGVILSFRSLAQEALRDVLSYHIPFLVSSIEDFKDHIPRETDMKVAMNVYE
  LSSAAGLPCEIDPALVVALSSQKSENISPEEEYKIACLLMVFVAVSLPTLASNVMSQYSP
  AIEGHCNNIHCLAKAINQIAAALFTIHKGSIEDRLKEFLALASSSLLKIGQETDKTTTRN
  RESVYLLLDMIVQESPFLTMDLLESCFPYVLLRNAYHAVYKQSVTSSA
• Function: Part of the WAVE complex that regulates lamellipodia formation. The WAVE complex regulates actin filament reorganization via its interaction with the Arp2/3 complex. Actin remodeling activity is regulated by RAC1. As component of the WAVE1 complex, required for BDNF-NTRK2 endocytic trafficking and signaling from early endosomes.
• Tissue Specificity: Expressed in all tissues examined except peripheral blood leukocytes, with highest expression in brain, heart, and skeletal muscle. Expressed in cells of various brain regions including Purkinje cells and dentate nucleus of the cerebellum, CA4 region and dentate gyrus of the hippocampus, and in frontal gray and white matter .
• KEGG Pathway:
  Regulation of actin cytoskeleton (hsa04810)
  Pathogenic Escherichia coli infection (hsa05130)
  Salmonella infection (hsa05132)
• Reactome Pathway:
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  RHO GTPases Activate WASPs and WAVEs (R-HSA-5663213)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RAC3 GTPase cycle (R-HSA-9013423)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[1]
Neurodevelopmental disorder	DIS372XH	Definitive	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Hypophosphatemia	DIS9DZYF	Strong	Altered Expression	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[6]
Psoriasis	DIS59VMN	Strong	Altered Expression	[7]
Thiel-Behnke corneal dystrophy	DIS3GK26	Strong	Biomarker	[8]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[9]
Neoplasm	DISZKGEW	moderate	Biomarker	[9]
Neuroblastoma	DISVZBI4	moderate	Altered Expression	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Artesunate	DMR27C8	Approved	Nck-associated protein 1 (NCKAP1) increases the response to substance of Artesunate.	[22]

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 Nck-associated protein 1 (NCKAP1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Nck-associated protein 1 (NCKAP1).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Nck-associated protein 1 (NCKAP1).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nck-associated protein 1 (NCKAP1).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Nck-associated protein 1 (NCKAP1).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Nck-associated protein 1 (NCKAP1).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Nck-associated protein 1 (NCKAP1).	[16]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Nck-associated protein 1 (NCKAP1).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Nck-associated protein 1 (NCKAP1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Nck-associated protein 1 (NCKAP1).	[20]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Nck-associated protein 1 (NCKAP1).	[21]

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] Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet. 2017 Apr;49(4):515-526. doi: 10.1038/ng.3792. Epub 2017 Feb 13.
• [3] Isolation of hNap1BP which interacts with human Nap1 (NCKAP1) whose expression is down-regulated in Alzheimer's disease.Gene. 2001 Jun 27;271(2):159-69. doi: 10.1016/s0378-1119(01)00521-2.
• [4] Arpin downregulation in breast cancer is associated with poor prognosis.Br J Cancer. 2016 Mar 1;114(5):545-53. doi: 10.1038/bjc.2016.18. Epub 2016 Feb 11.
• [5] Phosphatonin washout in Hyp mice proximal tubules: evidence for posttranscriptional regulation.Am J Physiol Renal Physiol. 2005 Feb;288(2):F363-70. doi: 10.1152/ajprenal.00217.2004. Epub 2004 Sep 28.
• [6] Nck-associated protein 1 associates with HSP90 to drive metastasis in human non-small-cell lung cancer.J Exp Clin Cancer Res. 2019 Mar 11;38(1):122. doi: 10.1186/s13046-019-1124-0.
• [7] Upper keratinocytes of psoriatic skin lesions express high levels of NAP-1/IL-8 mRNA in situ.J Invest Dermatol. 1991 Jul;97(1):73-9. doi: 10.1111/1523-1747.ep12478128.
• [8] Development of a Novel Vaccine Containing Binary Toxin for the Prevention of Clostridium difficile Disease with Enhanced Efficacy against NAP1 Strains.PLoS One. 2017 Jan 26;12(1):e0170640. doi: 10.1371/journal.pone.0170640. eCollection 2017.
• [9] NCKAP1 improves patient outcome and inhibits cell growth by enhancing Rb1/p53 activation in hepatocellular carcinoma.Cell Death Dis. 2019 May 8;10(5):369. doi: 10.1038/s41419-019-1603-4.
• [10] Human Nck-associated protein 1 and its binding protein affect the metabolism of beta-amyloid precursor protein with Swedish mutation.Neurosci Lett. 2001 Dec 4;316(1):50-4. doi: 10.1016/s0304-3940(01)02370-9.
• [11] 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.
• [12] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [13] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [14] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [15] 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.
• [16] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [17] 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.
• [18] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [19] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [20] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [21] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [22] Factors determining sensitivity or resistance of tumor cell lines towards artesunate. Chem Biol Interact. 2010 Apr 15;185(1):42-52.