Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF1VGJ9)

• DOT Name: Phosphatidylinositol 5-phosphate 4-kinase type-2 beta (PIP4K2B)
• Synonyms: EC 2.7.1.149; 1-phosphatidylinositol 5-phosphate 4-kinase 2-beta; Diphosphoinositide kinase 2-beta; Phosphatidylinositol 5-phosphate 4-kinase type II beta; PI(5)P 4-kinase type II beta; PIP4KII-beta; PtdIns(5)P-4-kinase isoform 2-beta
• Gene Name: PIP4K2B
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Breast neoplasm
  Pancreatic cancer
  Neoplasm
• UniProt ID: PI42B_HUMAN
• PDB ID: 1BO1; 3WZZ; 3X01; 3X02; 3X03; 3X04; 3X05; 3X06; 3X07; 3X08; 3X09; 3X0A; 3X0B; 3X0C; 6K4G; 6K4H; 7EM1; 7EM2; 7EM3; 7EM4; 7EM5; 7EM6; 7EM7; 7EM8; 7N80; 7N81
• EC Number: 2.7.1.149
• Pfam ID: PF01504
• Sequence:
  MSSNCTSTTAVAVAPLSASKTKTKKKHFVCQKVKLFRASEPILSVLMWGVNHTINELSNV
  PVPVMLMPDDFKAYSKIKVDNHLFNKENLPSRFKFKEYCPMVFRNLRERFGIDDQDYQNS
  VTRSAPINSDSQGRCGTRFLTTYDRRFVIKTVSSEDVAEMHNILKKYHQFIVECHGNTLL
  PQFLGMYRLTVDGVETYMVVTRNVFSHRLTVHRKYDLKGSTVAREASDKEKAKDLPTFKD
  NDFLNEGQKLHVGEESKKNFLEKLKRDVEFLAQLKIMDYSLLVGIHDVDRAEQEEMEVEE
  RAEDEECENDGVGGNLLCSYGTPPDSPGNLLSFPRFFGPGEFDPSVDVYAMKSHESSPKK
  EVYFMAIIDILTPYDTKKKAAHAAKTVKHGAGAEISTVNPEQYSKRFNEFMSNILT
• Function: Participates in the biosynthesis of phosphatidylinositol 4,5-bisphosphate. Preferentially utilizes GTP, rather than ATP, for PI(5)P phosphorylation and its activity reflects changes in direct proportion to the physiological GTP concentration. Its GTP-sensing activity is critical for metabolic adaptation. 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.
• Tissue Specificity: Highly expressed in brain, heart, pancreas, skeletal muscle and kidney. Detected at lower levels in placenta, lung and liver.
• 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

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[2]
Pancreatic cancer	DISJC981	moderate	Biomarker	[3]
Neoplasm	DISZKGEW	Limited	Altered Expression	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 beta (PIP4K2B).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 beta (PIP4K2B).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 beta (PIP4K2B).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 beta (PIP4K2B).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 beta (PIP4K2B).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 beta (PIP4K2B).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 beta (PIP4K2B).	[10]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 beta (PIP4K2B).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 beta (PIP4K2B).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 beta (PIP4K2B).	[13]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 beta (PIP4K2B).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 beta (PIP4K2B).	[16]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 beta (PIP4K2B).	[17]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone decreases the expression of Phosphatidylinositol 5-phosphate 4-kinase type-2 beta (PIP4K2B).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Phosphatidylinositol 5-phosphate 4-kinase type-2 beta (PIP4K2B).	[14]

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] Low PIP4K2B expression in human breast tumors correlates with reduced patient survival: A role for PIP4K2B in the regulation of E-cadherin expression.Cancer Res. 2013 Dec 1;73(23):6913-25. doi: 10.1158/0008-5472.CAN-13-0424. Epub 2013 Oct 14.
• [3] Long non-coding RNA PXN-AS1 suppresses pancreatic cancer progression by acting as a competing endogenous RNA of miR-3064 to upregulate PIP4K2B expression.J Exp Clin Cancer Res. 2019 Sep 5;38(1):390. doi: 10.1186/s13046-019-1379-5.
• [4] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] 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.
• [9] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [10] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [11] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [14] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [15] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [16] 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.
• [17] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [18] Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006 Oct;10(4):321-30.