Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI9UQSU)

• DOT Name: Phosphatidylinositol 4-kinase beta (PI4KB)
• Synonyms: PI4K-beta; PI4Kbeta; PtdIns 4-kinase beta; EC 2.7.1.67; NPIK; PI4K92; PI4KIII
• Gene Name: PI4KB
• Related Disease: Hearing loss, autosomal dominant 87
• UniProt ID: PI4KB_HUMAN
• PDB ID: 2N73; 4D0L; 4D0M; 4WAE; 4WAG; 5C46; 5C4G; 5EUQ; 5FBL; 5FBQ; 5FBR; 5FBV; 5FBW; 5LX2; 5NAS; 6GL3
• EC Number: 2.7.1.67
• Pfam ID: PF00454 ; PF21245
• Sequence:
  MGDTVVEPAPLKPTSEPTSGPPGNNGGSLLSVITEGVGELSVIDPEVAQKACQEVLEKVK
  LLHGGVAVSSRGTPLELVNGDGVDSEIRCLDDPPAQIREEEDEMGAAVASGTAKGARRRR
  QNNSAKQSWLLRLFESKLFDISMAISYLYNSKEPGVQAYIGNRLFCFRNEDVDFYLPQLL
  NMYIHMDEDVGDAIKPYIVHRCRQSINFSLQCALLLGAYSSDMHISTQRHSRGTKLRKLI
  LSDELKPAHRKRELPSLSPAPDTGLSPSKRTHQRSKSDATASISLSSNLKRTASNPKVEN
  EDEELSSSTESIDNSFSSPVRLAPEREFIKSLMAIGKRLATLPTKEQKTQRLISELSLLN
  HKLPARVWLPTAGFDHHVVRVPHTQAVVLNSKDKAPYLIYVEVLECENFDTTSVPARIPE
  NRIRSTRSVENLPECGITHEQRAGSFSTVPNYDNDDEAWSVDDIGELQVELPEVHTNSCD
  NISQFSVDSITSQESKEPVFIAAGDIRRRLSEQLAHTPTAFKRDPEDPSAVALKEPWQEK
  VRRIREGSPYGHLPNWRLLSVIVKCGDDLRQELLAFQVLKQLQSIWEQERVPLWIKPYKI
  LVISADSGMIEPVVNAVSIHQVKKQSQLSLLDYFLQEHGSYTTEAFLSAQRNFVQSCAGY
  CLVCYLLQVKDRHNGNILLDAEGHIIHIDFGFILSSSPRNLGFETSAFKLTTEFVDVMGG
  LDGDMFNYYKMLMLQGLIAARKHMDKVVQIVEIMQQGSQLPCFHGSSTIRNLKERFHMSM
  TEEQLQLLVEQMVDGSMRSITTKLYDGFQYLTNGIM
• Function: Phosphorylates phosphatidylinositol (PI) in the first committed step in the production of the second messenger inositol-1,4,5,-trisphosphate (PIP). May regulate Golgi disintegration/reorganization during mitosis, possibly via its phosphorylation. Involved in Golgi-to-plasma membrane trafficking. May play an important role in the inner ear development; (Microbial infection) Plays an essential role in Aichi virus RNA replication. Recruited by ACBD3 at the viral replication sites ; (Microbial infection) Required for cellular spike-mediated entry of human coronavirus SARS-CoV.
• Tissue Specificity: Widely expressed with highest levels in heart, skeletal muscle, pancreas, testis and ovary. Weakly expressed in liver . Expressed in the innear ear in the epithelium of the spinal organ of corti.
• 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)
• BioCyc Pathway: MetaCyc:HS07046-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hearing loss, autosomal dominant 87	DISIP6W8	Limited	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Phosphatidylinositol 4-kinase beta (PI4KB).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Phosphatidylinositol 4-kinase beta (PI4KB).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphatidylinositol 4-kinase beta (PI4KB).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Phosphatidylinositol 4-kinase beta (PI4KB).	[5]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Phosphatidylinositol 4-kinase beta (PI4KB).	[6]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Phosphatidylinositol 4-kinase beta (PI4KB).	[7]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Phosphatidylinositol 4-kinase beta (PI4KB).	[8]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Phosphatidylinositol 4-kinase beta (PI4KB).	[9]

2 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 affects the phosphorylation of Phosphatidylinositol 4-kinase beta (PI4KB).	[10]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Phosphatidylinositol 4-kinase beta (PI4KB).	[10]

References

• [1] Identification and functional characterization of two novel mutations in KCNJ10 and PI4KB in SeSAME syndrome without electrolyte imbalance. Hum Genomics. 2019 Oct 22;13(1):53. doi: 10.1186/s40246-019-0236-0.
• [2] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [3] 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.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [7] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [8] 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.
• [9] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [10] 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.