Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL9L6MX)

• DOT Name: Phosphatidylinositol 4-kinase type 2-alpha (PI4K2A)
• Synonyms: EC 2.7.1.67; Phosphatidylinositol 4-kinase type II-alpha
• Gene Name: PI4K2A
• Related Disease:
  Nervous system disease
  Hepatocellular carcinoma
  Advanced cancer
  Glioblastoma multiforme
  Breast cancer
  Breast carcinoma
  Hermansky-Pudlak syndrome
• UniProt ID: P4K2A_HUMAN
• PDB ID: 4HND; 4HNE; 4PLA; 4YC4; 5EUT; 5I0N
• EC Number: 2.7.1.67
• Pfam ID: PF00454
• Sequence:
  MDETSPLVSPERAQPPDYTFPSGSGAHFPQVPGGAVRVAAAAGSGPSPPGSPGHDRERQP
  LLDRARGAAAQGQTQTVAAQAQALAAQAAAAAHAAQAHRERNEFPEDPEFEAVVRQAELA
  IERCIFPERIYQGSSGSYFVKDPQGRIIAVFKPKNEEPYGHLNPKWTKWLQKLCCPCCFG
  RDCLVLNQGYLSEAGASLVDQKLELNIVPRTKVVYLASETFNYSAIDRVKSRGKRLALEK
  VPKVGQRFNRIGLPPKVGSFQLFVEGYKDADYWLRRFEAEPLPENTNRQLLLQFERLVVL
  DYIIRNTDRGNDNWLIKYDCPMDSSSSRDTDWVVVKEPVIKVAAIDNGLAFPLKHPDSWR
  AYPFYWAWLPQAKVPFSQEIKDLILPKISDPNFVKDLEEDLYELFKKDPGFDRGQFHKQI
  AVMRGQILNLTQALKDNKSPLHLVQMPPVIVETARSHQRSSSESYTQSFQSRKPFFSWW
• Function: Membrane-bound phosphatidylinositol-4 kinase (PI4-kinase) that catalyzes the phosphorylation of phosphatidylinositol (PI) to phosphatidylinositol 4-phosphate (PI4P), a lipid that plays important roles in endocytosis, Golgi function, protein sorting and membrane trafficking and is required for prolonged survival of neurons. Besides, phosphorylation of phosphatidylinositol (PI) to phosphatidylinositol 4-phosphate (PI4P) is the first committed step in the generation of phosphatidylinositol 4,5-bisphosphate (PIP2), a precursor of the second messenger inositol 1,4,5-trisphosphate (InsP3).
• Tissue Specificity: Widely expressed. Highest expression is observed in kidney, brain, heart, skeletal muscle, and placenta and lowest expression is observed in colon, thymus, and small intestine.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Phosphatidylinositol sig.ling system (hsa04070)
• Reactome Pathway:
  Synthesis of PIPs at the Golgi membrane (R-HSA-1660514)
  Synthesis of PIPs at the early endosome membrane (R-HSA-1660516)
  Synthesis of PIPs at the plasma membrane (R-HSA-1660499)
• BioCyc Pathway: MetaCyc:HS00573-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nervous system disease	DISJ7GGT	Definitive	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[3]
Glioblastoma multiforme	DISK8246	moderate	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Limited	Biomarker	[3]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[3]
Hermansky-Pudlak syndrome	DISCY0HQ	Limited	Biomarker	[5]

11 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 4-kinase type 2-alpha (PI4K2A).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Phosphatidylinositol 4-kinase type 2-alpha (PI4K2A).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Phosphatidylinositol 4-kinase type 2-alpha (PI4K2A).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Phosphatidylinositol 4-kinase type 2-alpha (PI4K2A).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Phosphatidylinositol 4-kinase type 2-alpha (PI4K2A).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phosphatidylinositol 4-kinase type 2-alpha (PI4K2A).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Phosphatidylinositol 4-kinase type 2-alpha (PI4K2A).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Phosphatidylinositol 4-kinase type 2-alpha (PI4K2A).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Phosphatidylinositol 4-kinase type 2-alpha (PI4K2A).	[13]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Phosphatidylinositol 4-kinase type 2-alpha (PI4K2A).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Phosphatidylinositol 4-kinase type 2-alpha (PI4K2A).	[17]

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 decreases the methylation of Phosphatidylinositol 4-kinase type 2-alpha (PI4K2A).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Phosphatidylinositol 4-kinase type 2-alpha (PI4K2A).	[16]

References

• [1] The Many Roles of Type II Phosphatidylinositol 4-Kinases in Membrane Trafficking: New Tricks for Old Dogs.Bioessays. 2018 Feb;40(2). doi: 10.1002/bies.201700145. Epub 2017 Dec 27.
• [2] Tetraspanin CD81-regulated cell motility plays a critical role in intrahepatic metastasis of hepatocellular carcinoma.Gastroenterology. 2008 Jul;135(1):244-256.e1. doi: 10.1053/j.gastro.2008.03.024. Epub 2008 Mar 21.
• [3] Therapeutic targeting of the PI4K2A/PKR lysosome network is critical for misfolded protein clearance and survival in cancer cells.Oncogene. 2020 Jan;39(4):801-813. doi: 10.1038/s41388-019-1010-4. Epub 2019 Sep 25.
• [4] Chromosomal Instability and Phosphoinositide Pathway Gene Signatures in Glioblastoma Multiforme.Mol Neurobiol. 2016 Jan;53(1):621-630. doi: 10.1007/s12035-014-9034-9. Epub 2014 Dec 15.
• [5] The WASH complex, an endosomal Arp2/3 activator, interacts with the Hermansky-Pudlak syndrome complex BLOC-1 and its cargo phosphatidylinositol-4-kinase type II.Mol Biol Cell. 2013 Jul;24(14):2269-84. doi: 10.1091/mbc.E13-02-0088. Epub 2013 May 15.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells. Nat Commun. 2018 Aug 9;9(1):3069. doi: 10.1038/s41467-018-05402-2.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [15] 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.
• [16] 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.
• [17] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.