Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9CMGMS)

• DOT Name: Inositol polyphosphate-5-phosphatase A (INPP5A)
• Synonyms: EC 3.1.3.56; 43 kDa inositol polyphosphate 5-phosphatase; Type I inositol 1,4,5-trisphosphate 5-phosphatase; 5PTase
• Gene Name: INPP5A
• Related Disease:
  Cardiovascular disease
  Cervical cancer
  Cutaneous squamous cell carcinoma
  Oculocerebrorenal syndrome
  Schizophrenia
  Sclerosing cholangitis
  Skin cancer
  Skin disease
  Squamous cell carcinoma
  Actinic keratosis
  Migraine disorder
  Neoplasm
• UniProt ID: I5P1_HUMAN
• EC Number: 3.1.3.56
• Sequence:
  MAGKAAAPGTAVLLVTANVGSLFDDPENLQKNWLREFYQVVHTHKPHFMALHCQEFGGKN
  YEASMSHVDKFVKELLSSDAMKEYNRARVYLDENYKSQEHFTALGSFYFLHESLKNIYQF
  DFKAKKYRKVAGKEIYSDTLESTPMLEKEKFPQDYFPECKWSRKGFIRTRWCIADCAFDL
  VNIHLFHDASNLVAWETSPSVYSGIRHKALGYVLDRIIDQRFEKVSYFVFGDFNFRLDSK
  SVVETLCTKATMQTVRAADTNEVVKLIFRESDNDRKVMLQLEKKLFDYFNQEVFRDNNGT
  ALLEFDKELSVFKDRLYELDISFPPSYPYSEDARQGEQYMNTRCPAWCDRILMSPSAKEL
  VLRSESEEKVVTYDHIGPNVCMGDHKPVFLAFRIMPGAGKPHAHVHKCCVVQ
• Function: Phosphatase that specifically hydrolyzes the 5-phosphate of inositol 1,4,5-trisphosphate to inositol 1,4-bisphosphate, and inositol 1,3,4,5-tetrasphosphate to inositol 1,3,4-trisphosphate. Plays a crucial role in the survival of cerebellar Purkinje cells.
• Tissue Specificity: Predominantly expressed in heart, brain, and skeletal muscle . In brain; high level in Purkinje cells .
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Phosphatidylinositol sig.ling system (hsa04070)
  Insulin sig.ling pathway (hsa04910)
• Reactome Pathway: Synthesis of IP2, IP, and Ins in the cytosol (R-HSA-1855183)
• BioCyc Pathway: MetaCyc:HS00936-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
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[1]
Cervical cancer	DISFSHPF	Strong	Biomarker	[2]
Cutaneous squamous cell carcinoma	DIS3LXUG	Strong	Altered Expression	[3]
Oculocerebrorenal syndrome	DIS8TEDY	Strong	Genetic Variation	[4]
Schizophrenia	DISSRV2N	Strong	Biomarker	[5]
Sclerosing cholangitis	DIS7GZNB	Strong	Genetic Variation	[6]
Skin cancer	DISTM18U	Strong	Genetic Variation	[7]
Skin disease	DISDW8R6	Strong	Biomarker	[7]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[7]
Actinic keratosis	DISR1RC5	Limited	Biomarker	[3]
Migraine disorder	DISFCQTG	Limited	Genetic Variation	[8]
Neoplasm	DISZKGEW	Limited	Altered Expression	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Inositol polyphosphate-5-phosphatase A (INPP5A).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Inositol polyphosphate-5-phosphatase A (INPP5A).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Inositol polyphosphate-5-phosphatase A (INPP5A).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Inositol polyphosphate-5-phosphatase A (INPP5A).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Inositol polyphosphate-5-phosphatase A (INPP5A).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Inositol polyphosphate-5-phosphatase A (INPP5A).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Inositol polyphosphate-5-phosphatase A (INPP5A).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Inositol polyphosphate-5-phosphatase A (INPP5A).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Inositol polyphosphate-5-phosphatase A (INPP5A).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Inositol polyphosphate-5-phosphatase A (INPP5A).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Inositol polyphosphate-5-phosphatase A (INPP5A).	[19]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Inositol polyphosphate-5-phosphatase A (INPP5A).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Inositol polyphosphate-5-phosphatase A (INPP5A).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Inositol polyphosphate-5-phosphatase A (INPP5A).	[22]

References

• [1] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [2] miR-181a-5p Promotes Proliferation and Invasion and Inhibits Apoptosis of Cervical Cancer Cells via Regulating Inositol Polyphosphate-5-Phosphatase A (INPP5A).Oncol Res. 2018 Jun 11;26(5):703-712. doi: 10.3727/096504017X14982569377511. Epub 2017 Jun 23.
• [3] Prognostic value of inositol polyphosphate-5-phosphatase expression in recurrent and metastatic cutaneous squamous cell carcinoma.J Am Acad Dermatol. 2020 Apr;82(4):846-853. doi: 10.1016/j.jaad.2019.08.027. Epub 2019 Aug 19.
• [4] The role of the inositol polyphosphate 5-phosphatases in cellular function and human disease.Biochem J. 2009 Apr 1;419(1):29-49. doi: 10.1042/BJ20081673.
• [5] Exome sequencing supports a de novo mutational paradigm for schizophrenia.Nat Genet. 2011 Aug 7;43(9):864-8. doi: 10.1038/ng.902.
• [6] Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):269-273. doi: 10.1038/ng.3745. Epub 2016 Dec 19.
• [7] A distinct and replicable variant of the squamous cell carcinoma gene inositol polyphosphate-5-phosphatase modifies the susceptibility of arsenic-associated skin lesions in Bangladesh. Cancer. 2015 Jul 1;121(13):2222-9. doi: 10.1002/cncr.29291. Epub 2015 Mar 10.
• [8] Detection and interpretation of shared genetic influences on 42 human traits.Nat Genet. 2016 Jul;48(7):709-17. doi: 10.1038/ng.3570. Epub 2016 May 16.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [16] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [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] 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.
• [21] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [22] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.