Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHRWR93)

• DOT Name: Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma (PIP4K2C)
• Synonyms: EC 2.7.1.149; Phosphatidylinositol 5-phosphate 4-kinase type II gamma; PI(5)P 4-kinase type II gamma; PIP4KII-gamma
• Gene Name: PIP4K2C
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Bipolar disorder
  Breast cancer
  Breast carcinoma
  Polycystic kidney disease
  Schizophrenia
  Tardive dyskinesia
  Type-1 diabetes
• UniProt ID: PI42C_HUMAN
• PDB ID: 2GK9; 7QIE; 7QPN; 8BQ4
• EC Number: 2.7.1.149
• Pfam ID: PF01504
• Sequence:
  MASSSVPPATVSAATAGPGPGFGFASKTKKKHFVQQKVKVFRAADPLVGVFLWGVAHSIN
  ELSQVPPPVMLLPDDFKASSKIKVNNHLFHRENLPSHFKFKEYCPQVFRNLRDRFGIDDQ
  DYLVSLTRNPPSESEGSDGRFLISYDRTLVIKEVSSEDIADMHSNLSNYHQYIVKCHGNT
  LLPQFLGMYRVSVDNEDSYMLVMRNMFSHRLPVHRKYDLKGSLVSREASDKEKVKELPTL
  KDMDFLNKNQKVYIGEEEKKIFLEKLKRDVEFLVQLKIMDYSLLLGIHDIIRGSEPEEEA
  PVREDESEVDGDCSLTGPPALVGSYGTSPEGIGGYIHSHRPLGPGEFESFIDVYAIRSAE
  GAPQKEVYFMGLIDILTQYDAKKKAAHAAKTVKHGAGAEISTVHPEQYAKRFLDFITNIF
  A
• Function: Phosphatidylinositol 5-phosphate 4-kinase with low enzymatic activity. May be a GTP sensor, has higher GTP-dependent kinase activity than ATP-dependent kinase activity. PIP4Ks negatively regulate insulin signaling through a catalytic-independent mechanism. They interact with PIP5Ks and suppress PIP5K-mediated PtdIns(4,5)P2 synthesis and insulin-dependent conversion to PtdIns(3,4,5)P3.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Phosphatidylinositol sig.ling system (hsa04070)
  Regulation of actin cytoskeleton (hsa04810)
• Reactome Pathway:
  PI5P Regulates TP53 Acetylation (R-HSA-6811555)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  Synthesis of PIPs in the nucleus (R-HSA-8847453)
  Synthesis of PIPs at the plasma membrane (R-HSA-1660499)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Polycystic kidney disease	DISWS3UY	Strong	Genetic Variation	[5]
Schizophrenia	DISSRV2N	Strong	Biomarker	[6]
Tardive dyskinesia	DISKA5RC	Strong	Biomarker	[6]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[7]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma (PIP4K2C) increases the response to substance of Arsenic trioxide.	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma (PIP4K2C).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma (PIP4K2C).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma (PIP4K2C).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma (PIP4K2C).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma (PIP4K2C).	[12]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma (PIP4K2C).	[13]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma (PIP4K2C).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma (PIP4K2C).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma (PIP4K2C).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma (PIP4K2C).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma (PIP4K2C).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma (PIP4K2C).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma (PIP4K2C).	[20]

References

• [1] PIP4K2A and PIP4K2C transcript levels are associated with cytogenetic risk and survival outcomes in acute myeloid leukemia.Cancer Genet. 2019 Apr;233-234:56-66. doi: 10.1016/j.cancergen.2019.04.002. Epub 2019 Apr 11.
• [2] Decrease in Multidrug Resistance-associated Protein 2 Activities by Knockdown of Phosphatidylinositol 4-phosphate 5-kinase in Hepatocytes and Cancer Cells.J Pharm Pharm Sci. 2019;22(1):576-584. doi: 10.18433/jpps30444.
• [3] Screening of PIP5K2A promoter region for mutations in bipolar disorder and schizophrenia.Psychiatr Genet. 2005 Sep;15(3):223-7. doi: 10.1097/00041444-200509000-00015.
• [4] The role of PIP5K1/pAKT and targeted inhibition of growth of subtypes of breast cancer using PIP5K1 inhibitor.Oncogene. 2019 Jan;38(3):375-389. doi: 10.1038/s41388-018-0438-2. Epub 2018 Aug 13.
• [5] 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.
• [6] Association study indicates a protective role of phosphatidylinositol-4-phosphate-5-kinase against tardive dyskinesia.Int J Neuropsychopharmacol. 2014 Dec 28;18(6):pyu098. doi: 10.1093/ijnp/pyu098.
• [7] Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus.Genes Immun. 2009 Mar;10(2):188-91. doi: 10.1038/gene.2008.99. Epub 2008 Dec 25.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [11] 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.
• [12] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [13] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [14] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] 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.
• [18] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [19] 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.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [21] Arsenic trioxide induces abnormal mitotic spindles through a PIP4KII/Rho pathway. Toxicol Sci. 2012 Jul;128(1):115-25. doi: 10.1093/toxsci/kfs129. Epub 2012 Apr 10.