Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT61Q7Q8)

• DOT Name: 5-azacytidine-induced protein 2 (AZI2)
• Synonyms: NF-kappa-B-activating kinase-associated protein 1; Nak-associated protein 1; Nap1; TILP
• Gene Name: AZI2
• Related Disease:
  Adult T-cell leukemia/lymphoma
  Advanced cancer
  Alzheimer disease
  Autoimmune disease
  Hypophosphatemia
  Non-small-cell lung cancer
  Psoriasis
  Substance abuse
  Thiel-Behnke corneal dystrophy
• UniProt ID: AZI2_HUMAN
• PDB ID: 5EP6; 5Z7G; 5Z7L; 7EA2; 7EA7
• Pfam ID: PF12845
• Sequence:
  MDALVEDDICILNHEKAHKRDTVTPVSIYSGDESVASHFALVTAYEDIKKRLKDSEKENS
  LLKKRIRFLEEKLIARFEEETSSVGREQVNKAYHAYREVCIDRDNLKSKLDKMNKDNSES
  LKVLNEQLQSKEVELLQLRTEVETQQVMRNLNPPSSNWEVEKLSCDLKIHGLEQELELMR
  KECSDLKIELQKAKQTDPYQEDNLKSRDLQKLSISSDNMQHAYWELKREMSNLHLVTQVQ
  AELLRKLKTSTAIKKACAPVGCSEDLGRDSTKLHLMNFTATYTRHPPLLPNGKALCHTTS
  SPLPGDVKVLSEKAILQSWTDNERSIPNDGTCFQEHSSYGRNSLEDNSWVFPSPPKSSET
  AFGETKTKTLPLPNLPPLHYLDQHNQNCLYKN
• Function: Adapter protein which binds TBK1 and IKBKE playing a role in antiviral innate immunity. Activates serine/threonine-protein kinase TBK1 and facilitates its oligomerization. Enhances the phosphorylation of NF-kappa-B p65 subunit RELA by TBK1. Promotes TBK1-induced as well as TNF-alpha or PMA-induced activation of NF-kappa-B. Participates in IFNB promoter activation via TICAM1.
• Tissue Specificity: Widely expressed . Abundant expression seen in the pancreas and testis .
• KEGG Pathway: RIG-I-like receptor sig.ling pathway (hsa04622)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[3]
Autoimmune disease	DISORMTM	Strong	Biomarker	[4]
Hypophosphatemia	DIS9DZYF	Strong	Altered Expression	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[6]
Psoriasis	DIS59VMN	Strong	Altered Expression	[7]
Substance abuse	DIS327VW	Strong	Biomarker	[8]
Thiel-Behnke corneal dystrophy	DIS3GK26	Strong	Biomarker	[9]

1 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 5-azacytidine-induced protein 2 (AZI2).	[10]

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 5-azacytidine-induced protein 2 (AZI2).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of 5-azacytidine-induced protein 2 (AZI2).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 5-azacytidine-induced protein 2 (AZI2).	[13]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of 5-azacytidine-induced protein 2 (AZI2).	[14]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of 5-azacytidine-induced protein 2 (AZI2).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of 5-azacytidine-induced protein 2 (AZI2).	[16]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of 5-azacytidine-induced protein 2 (AZI2).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of 5-azacytidine-induced protein 2 (AZI2).	[18]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of 5-azacytidine-induced protein 2 (AZI2).	[19]

References

• [1] SOX4 is a direct target gene of FRA-2 and induces expression of HDAC8 in adult T-cell leukemia/lymphoma.Blood. 2013 May 2;121(18):3640-9. doi: 10.1182/blood-2012-07-441022. Epub 2013 Mar 12.
• [2] Evaluation of the Cepheid Xpert Clostridium difficile Epi assay for diagnosis of Clostridium difficile infection and typing of the NAP1 strain at a cancer hospital.J Clin Microbiol. 2010 Dec;48(12):4519-24. doi: 10.1128/JCM.01648-10. Epub 2010 Oct 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] Capture Hi-C reveals novel candidate genes and complex long-range interactions with related autoimmune risk loci.Nat Commun. 2015 Nov 30;6:10069. doi: 10.1038/ncomms10069.
• [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] (AZI2)3'UTR Is a New SLC6A3 Downregulator Associated with an Epistatic Protection Against Substance Use Disorders.Mol Neurobiol. 2018 Jul;55(7):5611-5622. doi: 10.1007/s12035-017-0781-2. Epub 2017 Oct 5.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [13] 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.
• [14] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [15] 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.
• [16] 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.
• [17] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.