Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJF2AZ9)

• DOT Name: Phosphatidylinositol polyphosphate 5-phosphatase type IV (INPP5E)
• Synonyms: 72 kDa inositol polyphosphate 5-phosphatase; Inositol polyphosphate-5-phosphatase E; Phosphatidylinositol 4,5-bisphosphate 5-phosphatase; EC 3.1.3.36; Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase; EC 3.1.3.86
• Gene Name: INPP5E
• Related Disease:
  Joubert syndrome 1
  MORM syndrome
  Bardet biedl syndrome
  Ciliopathy
  COACH syndrome
  Cystic kidney disease
  Episodic kinesigenic dyskinesia 1
  Intellectual disability
  Meckel syndrome, type 1
  Neoplasm
  Neural tube defect
  Obesity
  Ocular motor apraxia, Cogan type
  Oculocerebrorenal syndrome
  Penile disorder
  Polycystic kidney disease
  Polydactyly
  Primary ciliary dyskinesia
  Melanoma
  Joubert syndrome
  Joubert syndrome with ocular defect
  Obsolete COACH syndrome 1
  Advanced cancer
  Medulloblastoma
• UniProt ID: INP5E_HUMAN
• PDB ID: 2XSW
• EC Number: 3.1.3.36; 3.1.3.86
• Sequence:
  MPSKAENLRPSEPAPQPPEGRTLQGQLPGAPPAQRAGSPPDAPGSESPALACSTPATPSG
  EDPPARAAPIAPRPPARPRLERALSLDDKGWRRRRFRGSQEDLEARNGTSPSRGSVQSEG
  PGAPAHSCSPPCLSTSLQEIPKSRGVLSSERGSPSSGGNPLSGVASSSPNLPHRDAAVAG
  SSPRLPSLLPPRPPPALSLDIASDSLRTANKVDSDLADYKLRAQPLLVRAHSSLGPGRPR
  SPLACDDCSLRSAKSSFSLLAPIRSKDVRSRSYLEGSLLASGALLGADELARYFPDRNVA
  LFVATWNMQGQKELPPSLDEFLLPAEADYAQDLYVIGVQEGCSDRREWETRLQETLGPHY
  VLLSSAAHGVLYMSLFIRRDLIWFCSEVECSTVTTRIVSQIKTKGALGISFTFFGTSFLF
  ITSHFTSGDGKVAERLLDYTRTVQALVLPRNVPDTNPYRSSAADVTTRFDEVFWFGDFNF
  RLSGGRTVVDALLCQGLVVDVPALLQHDQLIREMRKGSIFKGFQEPDIHFLPSYKFDIGK
  DTYDSTSKQRTPSYTDRVLYRSRHKGDICPVSYSSCPGIKTSDHRPVYGLFRVKVRPGRD
  NIPLAAGKFDRELYLLGIKRRISKEIQRQQALQSQNSSTICSVS
• Function: Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3), phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2). Specific for lipid substrates, inactive towards water soluble inositol phosphates. Plays an essential role in the primary cilium by controlling ciliary growth and phosphoinositide 3-kinase (PI3K) signaling and stability.
• Tissue Specificity: Detected in brain, heart, pancreas, testis and spleen.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Phosphatidylinositol sig.ling system (hsa04070)
• Reactome Pathway:
  ARL13B-mediated ciliary trafficking of INPP5E (R-HSA-5624958)
  Synthesis of PIPs at the Golgi membrane (R-HSA-1660514)
• BioCyc Pathway: MetaCyc:HS09270-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Joubert syndrome 1	DISC9Q82	Definitive	Autosomal recessive	[1]
MORM syndrome	DIS9NDA3	Definitive	Autosomal recessive	[2]
Bardet biedl syndrome	DISTBNZW	Strong	Genetic Variation	[2]
Ciliopathy	DIS10G4I	Strong	Biomarker	[3]
COACH syndrome	DISVDRSD	Strong	GermlineCausalMutation	[4]
Cystic kidney disease	DISRT1LM	Strong	Biomarker	[5]
Episodic kinesigenic dyskinesia 1	DISGVQMP	Strong	Biomarker	[6]
Intellectual disability	DISMBNXP	Strong	Biomarker	[2]
Meckel syndrome, type 1	DIS4YWZU	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Neural tube defect	DIS5J95E	Strong	Altered Expression	[9]
Obesity	DIS47Y1K	Strong	Therapeutic	[10]
Ocular motor apraxia, Cogan type	DIS32GGL	Strong	Genetic Variation	[11]
Oculocerebrorenal syndrome	DIS8TEDY	Strong	Biomarker	[12]
Penile disorder	DISI0KH5	Strong	Biomarker	[2]
Polycystic kidney disease	DISWS3UY	Strong	Genetic Variation	[13]
Polydactyly	DIS25BMZ	Strong	Biomarker	[14]
Primary ciliary dyskinesia	DISOBC7V	Strong	Biomarker	[2]
Melanoma	DIS1RRCY	moderate	Altered Expression	[15]
Joubert syndrome	DIS7P5CO	Supportive	Autosomal recessive	[4]
Joubert syndrome with ocular defect	DISDJVUI	Supportive	Autosomal recessive	[7]
Obsolete COACH syndrome 1	DISM57KK	Supportive	Autosomal recessive	[16]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[8]
Medulloblastoma	DISZD2ZL	Limited	Biomarker	[8]

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 Phosphatidylinositol polyphosphate 5-phosphatase type IV (INPP5E).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Phosphatidylinositol polyphosphate 5-phosphatase type IV (INPP5E).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Phosphatidylinositol polyphosphate 5-phosphatase type IV (INPP5E).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphatidylinositol polyphosphate 5-phosphatase type IV (INPP5E).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Phosphatidylinositol polyphosphate 5-phosphatase type IV (INPP5E).	[19]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Phosphatidylinositol polyphosphate 5-phosphatase type IV (INPP5E).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phosphatidylinositol polyphosphate 5-phosphatase type IV (INPP5E).	[22]

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] INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse. Nat Genet. 2009 Sep;41(9):1027-31. doi: 10.1038/ng.427. Epub 2009 Aug 9.
• [3] Induction of an Alternative mRNA 5' Leader Enhances Translation of the Ciliopathy Gene Inpp5e and Resistance to Oncolytic Virus Infection.Cell Rep. 2019 Dec 17;29(12):4010-4023.e5. doi: 10.1016/j.celrep.2019.11.072.
• [4] Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies. Nat Genet. 2009 Sep;41(9):1032-6. doi: 10.1038/ng.423. Epub 2009 Aug 9.
• [5] TMEM231, mutated in orofaciodigital and Meckel syndromes, organizes the ciliary transition zone. J Cell Biol. 2015 Apr 13;209(1):129-42. doi: 10.1083/jcb.201411087.
• [6] AKT signaling promotes DNA damage accumulation and proliferation in polycystic kidney disease.Hum Mol Genet. 2020 Jan 1;29(1):31-48. doi: 10.1093/hmg/ddz232.
• [7] Phenotypic spectrum and prevalence of INPP5E mutations in Joubert syndrome and related disorders. Eur J Hum Genet. 2013 Oct;21(10):1074-8. doi: 10.1038/ejhg.2012.305. Epub 2013 Feb 6.
• [8] A compartmentalized phosphoinositide signaling axis at cilia is regulated by INPP5E to maintain cilia and promote Sonic Hedgehog medulloblastoma.Oncogene. 2017 Oct 26;36(43):5969-5984. doi: 10.1038/onc.2017.208. Epub 2017 Jun 26.
• [9] Relationship Between INPP5E Gene Expression and Embryonic Neural Development in a Mouse Model of Neural Tube Defect.Med Sci Monit. 2018 Apr 7;24:2053-2059. doi: 10.12659/msm.906095.
• [10] Inhibition of 72 kDa inositol polyphosphate 5-phosphatase E improves insulin signal transduction in diet-induced obesity.J Endocrinol. 2013 Apr 15;217(2):131-40. doi: 10.1530/JOE-12-0562. Print 2013 May.
• [11] Role of reverse phenotyping in interpretation of next generation sequencing data and a review of INPP5E related disorders.Eur J Paediatr Neurol. 2016 Mar;20(2):286-295. doi: 10.1016/j.ejpn.2015.11.012. Epub 2015 Dec 18.
• [12] Functional overlap between murine Inpp5b and Ocrl1 may explain why deficiency of the murine ortholog for OCRL1 does not cause Lowe syndrome in mice.J Clin Invest. 1998 May 15;101(10):2042-53. doi: 10.1172/JCI2414.
• [13] Apical PtdIns(4,5)P(2) is required for ciliogenesis and suppression of polycystic kidney disease.FASEB J. 2019 Feb;33(2):2848-2857. doi: 10.1096/fj.201800385RRR. Epub 2018 Oct 15.
• [14] INPP5E regulates phosphoinositide-dependent cilia transition zone function.J Cell Biol. 2017 Jan 2;216(1):247-263. doi: 10.1083/jcb.201511055. Epub 2016 Dec 20.
• [15] PI(4,5)P2 5-phosphatase A regulates PI3K/Akt signalling and has a tumour suppressive role in human melanoma.Nat Commun. 2013;4:1508. doi: 10.1038/ncomms2489.
• [16] Joubert Syndrome. 2003 Jul 9 [updated 2017 Jun 29]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [17] 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.
• [18] 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.
• [19] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [20] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [21] 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.
• [22] 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.
• [23] 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.