Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8JQ1F7)

• DOT Name: Phosphatidylinositol 4-phosphate 5-kinase type-1 beta (PIP5K1B)
• Synonyms: PIP5K1-beta; PtdIns(4)P-5-kinase 1 beta; EC 2.7.1.68; Phosphatidylinositol 4-phosphate 5-kinase type I beta; PIP5KIbeta; Protein STM-7; Type I phosphatidylinositol 4-phosphate 5-kinase beta
• Gene Name: PIP5K1B
• Related Disease:
  Chronic renal failure
  Advanced cancer
  Osteoporosis
  Pancreatic cancer
  Type-1/2 diabetes
  Asthma
  Chronic kidney disease
  Friedreich's ataxia
• UniProt ID: PI51B_HUMAN
• EC Number: 2.7.1.68
• Pfam ID: PF01504
• Sequence:
  MSSAAENGEAAPGKQNEEKTYKKTASSAIKGAIQLGIGYTVGNLTSKPERDVLMQDFYVV
  ESVFLPSEGSNLTPAHHYPDFRFKTYAPLAFRYFRELFGIKPDDYLYSICSEPLIELSNP
  GASGSLFFVTSDDEFIIKTVQHKEAEFLQKLLPGYYMNLNQNPRTLLPKFYGLYCMQSGG
  INIRIVVMNNVLPRSMRMHFTYDLKGSTYKRRASRKEREKSNPTFKDLDFLQDMHEGLYF
  DTETYNALMKTLQRDCRVLESFKIMDYSLLLGIHFLDHSLKEKEEETPQNVPDAKRTGMQ
  KVLYSTAMESIQGPGKSGDGIITENPDTMGGIPAKSHRGEKLLLFMGIIDILQSYRLMKK
  LEHSWKALVYDGDTVSVHRPSFYADRFLKFMNSRVFKKIQALKASPSKKRCNSIAALKAT
  SQEIVSSISQEWKDEKRDLLTEGQSFSSLDEEALGSRHRPDLVPSTPSLFEAASLATTIS
  SSSLYVNEHYPHDRPTLYSNSKGLPSSSTFTLEEGTIYLTAEPNTLEVQDDNASVLDVYL
• Function: Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate (PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2/PIP2), a lipid second messenger that regulates several cellular processes such as signal transduction, vesicle trafficking, actin cytoskeleton dynamics, cell adhesion, and cell motility. PtdIns(4,5)P2 can directly act as a second messenger or can be utilized as a precursor to generate other second messengers: inositol 1,4,5-trisphosphate (IP3), diacylglycerol (DAG) or phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3/PIP3). Mediates RAC1-dependent reorganization of actin filaments. Contributes to the activation of phospholipase PLD2. Together with PIP5K1A, is required, after stimulation by G-protein coupled receptors, for the synthesis of IP3 that will induce stable platelet adhesion.
• Tissue Specificity: Detected in heart, pancreas, brain, kidney, skeletal muscle and lung.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Phosphatidylinositol sig.ling system (hsa04070)
  Phospholipase D sig.ling pathway (hsa04072)
  Endocytosis (hsa04144)
  Focal adhesion (hsa04510)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Regulation of actin cytoskeleton (hsa04810)
  Yersinia infection (hsa05135)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  WNT mediated activation of DVL (R-HSA-201688)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  Synthesis of PIPs at the plasma membrane (R-HSA-1660499)
• BioCyc Pathway: MetaCyc:HS02982-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Osteoporosis	DISF2JE0	Strong	Biomarker	[3]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[4]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[5]
Asthma	DISW9QNS	Limited	Biomarker	[6]
Chronic kidney disease	DISW82R7	Limited	Genetic Variation	[7]
Friedreich's ataxia	DIS5DV35	Limited	Posttranslational Modification	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Phosphatidylinositol 4-phosphate 5-kinase type-1 beta (PIP5K1B) affects the response to substance of Etoposide.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Phosphatidylinositol 4-phosphate 5-kinase type-1 beta (PIP5K1B).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phosphatidylinositol 4-phosphate 5-kinase type-1 beta (PIP5K1B).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Phosphatidylinositol 4-phosphate 5-kinase type-1 beta (PIP5K1B).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phosphatidylinositol 4-phosphate 5-kinase type-1 beta (PIP5K1B).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphatidylinositol 4-phosphate 5-kinase type-1 beta (PIP5K1B).	[13]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Phosphatidylinositol 4-phosphate 5-kinase type-1 beta (PIP5K1B).	[14]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Phosphatidylinositol 4-phosphate 5-kinase type-1 beta (PIP5K1B).	[15]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Phosphatidylinositol 4-phosphate 5-kinase type-1 beta (PIP5K1B).	[16]
Cholecalciferol	DMGU74E	Approved	Cholecalciferol affects the expression of Phosphatidylinositol 4-phosphate 5-kinase type-1 beta (PIP5K1B).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Phosphatidylinositol 4-phosphate 5-kinase type-1 beta (PIP5K1B).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phosphatidylinositol 4-phosphate 5-kinase type-1 beta (PIP5K1B).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Phosphatidylinositol 4-phosphate 5-kinase type-1 beta (PIP5K1B).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Phosphatidylinositol 4-phosphate 5-kinase type-1 beta (PIP5K1B).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Phosphatidylinositol 4-phosphate 5-kinase type-1 beta (PIP5K1B).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Phosphatidylinositol 4-phosphate 5-kinase type-1 beta (PIP5K1B).	[21]

References

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• [3] PIP5k1 controls bone homeostasis through modulating both osteoclast and osteoblast differentiation.J Mol Cell Biol. 2020 Jan 22;12(1):55-70. doi: 10.1093/jmcb/mjz028.
• [4] Cloning of novel transcripts of the human guanine-nucleotide-exchange factor Mss4: in situ chromosomal mapping and expression in pancreatic cancer.Genomics. 1997 Dec 15;46(3):389-96. doi: 10.1006/geno.1997.5049.
• [5] Mapping eGFR loci to the renal transcriptome and phenome in the VA Million Veteran Program.Nat Commun. 2019 Aug 26;10(1):3842. doi: 10.1038/s41467-019-11704-w.
• [6] Vitamin D related genes in lung development and asthma pathogenesis.BMC Med Genomics. 2013 Nov 5;6:47. doi: 10.1186/1755-8794-6-47.
• [7] Genome-wide association and functional follow-up reveals new loci for kidney function.PLoS Genet. 2012;8(3):e1002584. doi: 10.1371/journal.pgen.1002584. Epub 2012 Mar 29.
• [8] Cis-silencing of PIP5K1B evidenced in Friedreich's ataxia patient cells results in cytoskeleton anomalies.Hum Mol Genet. 2013 Jul 15;22(14):2894-904. doi: 10.1093/hmg/ddt144. Epub 2013 Apr 2.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [12] 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.
• [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] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [15] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [16] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [17] Targeting iron homeostasis induces cellular differentiation and synergizes with differentiating agents in acute myeloid leukemia. J Exp Med. 2010 Apr 12;207(4):731-50. doi: 10.1084/jem.20091488. Epub 2010 Apr 5.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] 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.
• [21] 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.
• [22] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [23] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [24] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.