Details of Drug Off-Target (DOT)

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

• DOT Name: Inositol-trisphosphate 3-kinase B (ITPKB)
• Synonyms: EC 2.7.1.127; Inositol 1,4,5-trisphosphate 3-kinase B; IP3 3-kinase B; IP3K B; InsP 3-kinase B
• Gene Name: ITPKB
• Related Disease:
  Lung cancer
  Lung carcinoma
  Acute myelogenous leukaemia
  Advanced cancer
  Alzheimer disease
  Arrhythmia
  B-cell neoplasm
  Dental caries
  Neoplasm
  ITPKB deficiency
  Parkinson disease
  Tourette syndrome
• UniProt ID: IP3KB_HUMAN
• EC Number: 2.7.1.127
• Pfam ID: PF03770
• Sequence:
  MAVYCYALNSLVIMNSANEMKSGGGPGPSGSETPPPPRRAVLSPGSVFSPGRGASFLFPP
  AESLSPEEPRSPGGWRSGRRRLNSSSGSGSGSSGSSVSSPSWAGRLRGDRQQVVAAGTLS
  PPGPEEAKRKLRILQRELQNVQVNQKVGMFEAHIQAQSSAIQAPRSPRLGRARSPSPCPF
  RSSSQPPGRVLVQGARSEERRTKSWGEQCPETSGTDSGRKGGPSLCSSQVKKGMPPLPGR
  AAPTGSEAQGPSAFVRMEKGIPASPRCGSPTAMEIDKRGSPTPGTRSCLAPSLGLFGASL
  TMATEVAARVTSTGPHRPQDLALTEPSGRARELEDLQPPEALVERQGQFLGSETSPAPER
  GGPRDGEPPGKMGKGYLPCGMPGSGEPEVGKRPEETTVSVQSAESSDSLSWSRLPRALAS
  VGPEEARSGAPVGGGRWQLSDRVEGGSPTLGLLGGSPSAQPGTGNVEAGIPSGRMLEPLP
  CWDAAKDLKEPQCPPGDRVGVQPGNSRVWQGTMEKAGLAWTRGTGVQSEGTWESQRQDSD
  ALPSPELLPQDPDKPFLRKACSPSNIPAVIITDMGTQEDGALEETQGSPRGNLPLRKLSS
  SSASSTGFSSSYEDSEEDISSDPERTLDPNSAFLHTLDQQKPRVSKSWRKIKNMVHWSPF
  VMSFKKKYPWIQLAGHAGSFKAAANGRILKKHCESEQRCLDRLMVDVLRPFVPAYHGDVV
  KDGERYNQMDDLLADFDSPCVMDCKMGIRTYLEEELTKARKKPSLRKDMYQKMIEVDPEA
  PTEEEKAQRAVTKPRYMQWRETISSTATLGFRIEGIKKEDGTVNRDFKKTKTREQVTEAF
  REFTKGNHNILIAYRDRLKAIRTTLEVSPFFKCHEVIGSSLLFIHDKKEQAKVWMIDFGK
  TTPLPEGQTLQHDVPWQEGNREDGYLSGLNNLVDILTEMSQDAPLA
• Function: Catalyzes the phosphorylation of 1D-myo-inositol 1,4,5-trisphosphate (InsP3) into 1D-myo-inositol 1,3,4,5-tetrakisphosphate and participates to the regulation of calcium homeostasis.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Calcium sig.ling pathway (hsa04020)
  Phosphatidylinositol sig.ling system (hsa04070)
• Reactome Pathway: Synthesis of IP3 and IP4 in the cytosol (R-HSA-1855204)
• BioCyc Pathway: MetaCyc:HS07103-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung cancer	DISCM4YA	Definitive	Biomarker	[1]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[4]
Arrhythmia	DISFF2NI	Strong	Biomarker	[5]
B-cell neoplasm	DISVY326	Strong	Genetic Variation	[6]
Dental caries	DISRBCMD	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
ITPKB deficiency	DISS9339	Limited	Autosomal recessive	[8]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[9]
Tourette syndrome	DISX9D54	No Known	Unknown	[10]

8 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 Inositol-trisphosphate 3-kinase B (ITPKB).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Inositol-trisphosphate 3-kinase B (ITPKB).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Inositol-trisphosphate 3-kinase B (ITPKB).	[13]
Marinol	DM70IK5	Approved	Marinol increases the expression of Inositol-trisphosphate 3-kinase B (ITPKB).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Inositol-trisphosphate 3-kinase B (ITPKB).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Inositol-trisphosphate 3-kinase B (ITPKB).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Inositol-trisphosphate 3-kinase B (ITPKB).	[18]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Inositol-trisphosphate 3-kinase B (ITPKB).	[20]

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 increases the methylation of Inositol-trisphosphate 3-kinase B (ITPKB).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Inositol-trisphosphate 3-kinase B (ITPKB).	[19]

References

• [1] Effect of the actin- and calcium-regulating activities of ITPKB on the metastatic potential of lung cancer cells.Biochem J. 2018 Jun 26;475(12):2057-2071. doi: 10.1042/BCJ20180238.
• [2] A novel retroviral mutagenesis screen identifies prognostic genes in RUNX1 mediated myeloid leukemogenesis.Oncotarget. 2015 Oct 13;6(31):30664-74. doi: 10.18632/oncotarget.5133.
• [3] Inositol-triphosphate 3-kinase B confers cisplatin resistance by regulating NOX4-dependent redox balance.J Clin Invest. 2019 May 13;129(6):2431-2445. doi: 10.1172/JCI124550. eCollection 2019 May 13.
• [4] miR-132 loss de-represses ITPKB and aggravates amyloid and TAU pathology in Alzheimer's brain.EMBO Mol Med. 2016 Sep 1;8(9):1005-18. doi: 10.15252/emmm.201606520. Print 2016 Sep.
• [5] Apelin shorten QT interval by inhibiting Kir2.1/I(K1) via a PI3K way in acute myocardial infarction.Biochem Biophys Res Commun. 2019 Sep 17;517(2):272-277. doi: 10.1016/j.bbrc.2019.07.041. Epub 2019 Jul 23.
• [6] Acalabrutinib for adults with mantle cell lymphoma.Expert Rev Clin Pharmacol. 2019 Mar;12(3):179-187. doi: 10.1080/17512433.2019.1568868. Epub 2019 Jan 26.
• [7] Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data.Nat Commun. 2019 Jun 24;10(1):2773. doi: 10.1038/s41467-019-10630-1.
• [8] 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.
• [9] ITPKB and ZNF184 are associated with Parkinson's disease risk in East Asians.Neurobiol Aging. 2020 Feb;86:201.e15-201.e17. doi: 10.1016/j.neurobiolaging.2019.01.026. Epub 2019 Feb 2.
• [10] 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.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [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] 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.
• [15] 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.
• [16] 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.
• [17] BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol. 2012 Dec;92(6):1147-54. doi: 10.1189/jlb.0312165. Epub 2012 Jul 16.
• [18] 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.
• [19] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [20] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.