Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT73T6T6)

• DOT Name: Inositol-trisphosphate 3-kinase C (ITPKC)
• Synonyms: EC 2.7.1.127; Inositol 1,4,5-trisphosphate 3-kinase C; IP3 3-kinase C; IP3K C; InsP 3-kinase C
• Gene Name: ITPKC
• Related Disease:
  Cervical cancer
  Cervical carcinoma
  Nephropathy
  Hirschsprung disease
• UniProt ID: IP3KC_HUMAN
• PDB ID: 2A98
• EC Number: 2.7.1.127
• Pfam ID: PF03770
• Sequence:
  MRRCPCRGSLNEAEAGALPAAARMGLEAPRGGRRRQPGQQRPGPGAGAPAGRPEGGGPWA
  RTEGSSLHSEPERAGLGPAPGTESPQAEFWTDGQTEPAAAGLGVETERPKQKTEPDRSSL
  RTHLEWSWSELETTCLWTETGTDGLWTDPHRSDLQFQPEEASPWTQPGVHGPWTELETHG
  SQTQPERVKSWADNLWTHQNSSSLQTHPEGACPSKEPSADGSWKELYTDGSRTQQDIEGP
  WTEPYTDGSQKKQDTEAARKQPGTGGFQIQQDTDGSWTQPSTDGSQTAPGTDCLLGEPED
  GPLEEPEPGELLTHLYSHLKCSPLCPVPRLIITPETPEPEAQPVGPPSRVEGGSGGFSSA
  SSFDESEDDVVAGGGGASDPEDRSGSKPWKKLKTVLKYSPFVVSFRKHYPWVQLSGHAGN
  FQAGEDGRILKRFCQCEQRSLEQLMKDPLRPFVPAYYGMVLQDGQTFNQMEDLLADFEGP
  SIMDCKMGSRTYLEEELVKARERPRPRKDMYEKMVAVDPGAPTPEEHAQGAVTKPRYMQW
  RETMSSTSTLGFRIEGIKKADGTCNTNFKKTQALEQVTKVLEDFVDGDHVILQKYVACLE
  ELREALEISPFFKTHEVVGSSLLFVHDHTGLAKVWMIDFGKTVALPDHQTLSHRLPWAEG
  NREDGYLWGLDNMICLLQGLAQS
• 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. Can phosphorylate inositol 2,4,5-triphosphate to inositol 2,4,5,6-tetraphosphate.
• Tissue Specificity: Highly expressed in pancreas, skeletal muscle, liver, placenta and weakly in kidney and brain.
• 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:HS01533-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cervical cancer	DISFSHPF	Definitive	Genetic Variation	[1]
Cervical carcinoma	DIST4S00	Definitive	Genetic Variation	[1]
Nephropathy	DISXWP4P	Definitive	Genetic Variation	[2]
Hirschsprung disease	DISUUSM1	moderate	Genetic Variation	[3]

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 Inositol-trisphosphate 3-kinase C (ITPKC).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Inositol-trisphosphate 3-kinase C (ITPKC).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Inositol-trisphosphate 3-kinase C (ITPKC).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Inositol-trisphosphate 3-kinase C (ITPKC).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Inositol-trisphosphate 3-kinase C (ITPKC).	[8]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Inositol-trisphosphate 3-kinase C (ITPKC).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Inositol-trisphosphate 3-kinase C (ITPKC).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Inositol-trisphosphate 3-kinase C (ITPKC).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Inositol-trisphosphate 3-kinase C (ITPKC).	[11]

References

• [1] Genetic polymorphisms in the ITPKC gene and cervical squamous cell carcinoma risk.Cancer Immunol Immunother. 2012 Nov;61(11):2153-9. doi: 10.1007/s00262-012-1280-y. Epub 2012 May 18.
• [2] Study of the association between ITPKC genetic polymorphisms and calcium nephrolithiasis.Biomed Res Int. 2014;2014:397826. doi: 10.1155/2014/397826. Epub 2014 Mar 3.
• [3] Potential association between ITPKC genetic variations and Hirschsprung disease.Mol Biol Rep. 2017 Jul;44(3):307-313. doi: 10.1007/s11033-017-4111-6. Epub 2017 Jun 29.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Quercetin induced cell apoptosis and altered gene expression in AGS human gastric cancer cells. Environ Toxicol. 2018 Nov;33(11):1168-1181. doi: 10.1002/tox.22623. Epub 2018 Aug 27.
• [8] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.