Details of Drug Off-Target (DOT)

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

• DOT Name: Inositol polyphosphate 5-phosphatase K (INPP5K)
• Synonyms: EC 3.1.3.56; Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase; EC 3.1.3.86; Phosphatidylinositol-4,5-bisphosphate 5-phosphatase; EC 3.1.3.36; Skeletal muscle and kidney-enriched inositol phosphatase
• Gene Name: INPP5K
• Related Disease:
  Coronary heart disease
  Adult glioblastoma
  Aicardi-Goutieres syndrome
  Alzheimer disease
  Anxiety
  Anxiety disorder
  Arteriosclerosis
  Atherosclerosis
  Bladder cancer
  Cardiovascular disease
  Cataract
  Congenital muscular dystrophy with cataracts and intellectual disability
  Dementia
  Depression
  Fragile X syndrome
  Frontonasal dysplasia
  Gaucher disease
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Mental disorder
  Muscular dystrophy
  Oculocerebrorenal syndrome
  Skin cancer
  Skin carcinoma
  Tauopathy
  Urinary bladder cancer
  Urinary bladder neoplasm
  Congenital muscular dystrophy
  Cutaneous melanoma
  Melanoma
  Marinesco-Sjogren syndrome
  Breast carcinoma
  Gastric cancer
  Intellectual disability
  Neoplasm
  Parkinson disease
  Stomach cancer
• UniProt ID: INP5K_HUMAN
• EC Number: 3.1.3.36; 3.1.3.56; 3.1.3.86
• Pfam ID: PF17751
• Sequence:
  MSSRKLSGPKGRRLSIHVVTWNVASAAPPLDLSDLLQLNNRNLNLDIYVIGLQELNSGII
  SLLSDAAFNDSWSSFLMDVLSPLSFIKVSHVRMQGILLLVFAKYQHLPYIQILSTKSTPT
  GLFGYWGNKGGVNICLKLYGYYVSIINCHLPPHISNNYQRLEHFDRILEMQNCEGRDIPN
  ILDHDLIIWFGDMNFRIEDFGLHFVRESIKNRCYGGLWEKDQLSIAKKHDPLLREFQEGR
  LLFPPTYKFDRNSNDYDTSEKKRKPAWTDRILWRLKRQPCAGPDTPIPPASHFSLSLRGY
  SSHMTYGISDHKPVSGTFDLELKPLVSAPLIVLMPEDLWTVENDMMVSYSSTSDFPSSPW
  DWIGLYKVGLRDVNDYVSYAWVGDSKVSCSDNLNQVYIDISNIPTTEDEFLLCYYSNSLR
  SVVGISRPFQIPPGSLREDPLGEAQPQI
• Function: Inositol 5-phosphatase which acts on inositol 1,4,5-trisphosphate, inositol 1,3,4,5-tetrakisphosphate, phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. Has 6-fold higher affinity for phosphatidylinositol 4,5-bisphosphate than for inositol 1,4,5-trisphosphate. Negatively regulates assembly of the actin cytoskeleton. Controls insulin-dependent glucose uptake among inositol 3,4,5-trisphosphate phosphatases; therefore, is the specific regulator for insulin signaling in skeletal muscle.
• Tissue Specificity: Ubiquitously expressed with highest levels in skeletal muscle, heart and kidney.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Synthesis of PIPs at the plasma membrane (R-HSA-1660499)
• BioCyc Pathway: MetaCyc:HS05626-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coronary heart disease	DIS5OIP1	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[2]
Aicardi-Goutieres syndrome	DIS1NH4X	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[4]
Anxiety	DISIJDBA	Strong	Biomarker	[5]
Anxiety disorder	DISBI2BT	Strong	Biomarker	[5]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[6]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[6]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[7]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[8]
Cataract	DISUD7SL	Strong	Genetic Variation	[9]
Congenital muscular dystrophy with cataracts and intellectual disability	DISQE8QF	Strong	Autosomal recessive	[10]
Dementia	DISXL1WY	Strong	Biomarker	[11]
Depression	DIS3XJ69	Strong	Biomarker	[5]
Fragile X syndrome	DISE8W3A	Strong	Genetic Variation	[11]
Frontonasal dysplasia	DISXV4YX	Strong	Biomarker	[12]
Gaucher disease	DISTW5JG	Strong	Biomarker	[13]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[14]
Mental disorder	DIS3J5R8	Strong	Biomarker	[15]
Muscular dystrophy	DISJD6P7	Strong	Genetic Variation	[9]
Oculocerebrorenal syndrome	DIS8TEDY	Strong	Biomarker	[16]
Skin cancer	DISTM18U	Strong	Biomarker	[17]
Skin carcinoma	DISUZREN	Strong	Genetic Variation	[18]
Tauopathy	DISY2IPA	Strong	Altered Expression	[4]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[7]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[7]
Congenital muscular dystrophy	DISKY7OY	moderate	Genetic Variation	[19]
Cutaneous melanoma	DIS3MMH9	moderate	Biomarker	[20]
Melanoma	DIS1RRCY	moderate	Biomarker	[20]
Marinesco-Sjogren syndrome	DISKEU0B	Supportive	Autosomal recessive	[21]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[22]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[23]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[9]
Neoplasm	DISZKGEW	Limited	Altered Expression	[24]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[25]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[23]

1 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 K (INPP5K).	[26]

10 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 Inositol polyphosphate 5-phosphatase K (INPP5K).	[27]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Inositol polyphosphate 5-phosphatase K (INPP5K).	[28]
Selenium	DM25CGV	Approved	Selenium increases the expression of Inositol polyphosphate 5-phosphatase K (INPP5K).	[29]
Glucosamine	DM4ZLFD	Approved	Glucosamine increases the expression of Inositol polyphosphate 5-phosphatase K (INPP5K).	[30]
Exemestane	DM9HPW3	Approved	Exemestane increases the expression of Inositol polyphosphate 5-phosphatase K (INPP5K).	[31]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Inositol polyphosphate 5-phosphatase K (INPP5K).	[32]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Inositol polyphosphate 5-phosphatase K (INPP5K).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Inositol polyphosphate 5-phosphatase K (INPP5K).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Inositol polyphosphate 5-phosphatase K (INPP5K).	[34]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Inositol polyphosphate 5-phosphatase K (INPP5K).	[35]

References

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• [2] Lipid phosphatases SKIP and SHIP2 regulate fibronectin-dependent cell migration in glioblastoma.FEBS J. 2019 Mar;286(6):1120-1135. doi: 10.1111/febs.14769. Epub 2019 Feb 16.
• [3] A precisely regulated gene expression cassette potently modulates metastasis and survival in multiple solid cancers.PLoS Genet. 2008 Jul 18;4(7):e1000129. doi: 10.1371/journal.pgen.1000129.
• [4] A Novel Microtubule-Tau Association Enhancer and Neuroprotective Drug Candidate: Ac-SKIP.Front Cell Neurosci. 2019 Oct 1;13:435. doi: 10.3389/fncel.2019.00435. eCollection 2019.
• [5] Determining Factors for Stress Perception Assessed with the Perceived Stress Scale (PSS-4) in Spanish and Other European Samples.Front Psychol. 2018 Jan 26;9:37. doi: 10.3389/fpsyg.2018.00037. eCollection 2018.
• [6] Celastrol-loaded PEG-b-PPS nanocarriers as an anti-inflammatory treatment for atherosclerosis.Biomater Sci. 2019 Jan 29;7(2):657-668. doi: 10.1039/c8bm01224e.
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• [8] Long-term effects of total and source-specific particulate air pollution on incident cardiovascular disease in Gothenburg, Sweden.Environ Res. 2017 Oct;158:61-71. doi: 10.1016/j.envres.2017.05.036. Epub 2017 Jun 8.
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• [12] Potocki-Shaffer deletion encompassing ALX4 in a patient with frontonasal dysplasia phenotype.Am J Med Genet A. 2014 Feb;164A(2):346-52. doi: 10.1002/ajmg.a.36140. Epub 2013 Dec 13.
• [13] Efficacy of pentosan polysulfate in in vitro models of lysosomal storage disorders: Fabry and Gaucher Disease.PLoS One. 2019 May 31;14(5):e0217780. doi: 10.1371/journal.pone.0217780. eCollection 2019.
• [14] High SKIP expression is correlated with poor prognosis and cell proliferation of hepatocellular carcinoma.Med Oncol. 2013;30(3):537. doi: 10.1007/s12032-013-0537-4. Epub 2013 May 22.
• [15] Audio-visual sensory deprivation degrades visuo-tactile peri-personal space.Conscious Cogn. 2018 May;61:61-75. doi: 10.1016/j.concog.2018.04.001. Epub 2018 Apr 10.
• [16] 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.
• [17] Melanocortin-1 receptor, skin cancer and phenotypic characteristics (M-SKIP) project: study design and methods for pooling results of genetic epidemiological studies.BMC Med Res Methodol. 2012 Aug 3;12:116. doi: 10.1186/1471-2288-12-116.
• [18] MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M-SKIP project.Br J Cancer. 2015 Jul 14;113(2):354-63. doi: 10.1038/bjc.2015.231. Epub 2015 Jun 23.
• [19] Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjgren Syndrome and Dystroglycanopathy.Am J Hum Genet. 2017 Mar 2;100(3):537-545. doi: 10.1016/j.ajhg.2017.01.019. Epub 2017 Feb 9.
• [20] MC1R variants increased the risk of sporadic cutaneous melanoma in darker-pigmented Caucasians: a pooled-analysis from the M-SKIP project.Int J Cancer. 2015 Feb 1;136(3):618-31. doi: 10.1002/ijc.29018. Epub 2014 Jun 18.
• [21] Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment. Am J Hum Genet. 2017 Mar 2;100(3):523-536. doi: 10.1016/j.ajhg.2017.01.024. Epub 2017 Feb 9.
• [22] Expression and prognostic role of SKIP in human breast carcinoma.J Mol Histol. 2014 Apr;45(2):169-80. doi: 10.1007/s10735-013-9546-z. Epub 2013 Oct 23.
• [23] Evaluation of MT Family Isoforms as Potential Biomarker for Predicting Progression and Prognosis in Gastric Cancer.Biomed Res Int. 2019 Jul 17;2019:2957821. doi: 10.1155/2019/2957821. eCollection 2019.
• [24] Differential SKIP expression in PTEN-deficient glioblastoma regulates cellular proliferation and migration.Oncogene. 2015 Jul;34(28):3711-27. doi: 10.1038/onc.2014.303. Epub 2014 Sep 22.
• [25] Genome-wide variant by serum urate interaction in Parkinson's disease.Ann Neurol. 2015 Nov;78(5):731-41. doi: 10.1002/ana.24504. Epub 2015 Aug 29.
• [26] 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.
• [27] 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.
• [28] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [29] 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.
• [30] NGBR is required to ameliorate type 2 diabetes in mice by enhancing insulin sensitivity. J Biol Chem. 2021 Jan-Jun;296:100624. doi: 10.1016/j.jbc.2021.100624. Epub 2021 Apr 2.
• [31] Effects of aromatase inhibitors on human osteoblast and osteoblast-like cells: a possible androgenic bone protective effects induced by exemestane. Bone. 2007 Apr;40(4):876-87. doi: 10.1016/j.bone.2006.11.029. Epub 2006 Dec 28.
• [32] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [33] 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.
• [34] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [35] 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.