Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV2NPHG)

• DOT Name: WD repeat domain phosphoinositide-interacting protein 1
• Synonyms: WIPI-1; Atg18 protein homolog; WD40 repeat protein interacting with phosphoinositides of 49 kDa; WIPI 49 kDa
• Gene Name: WIPI1
• UniProt ID: WIPI1_HUMAN
• Pfam ID: PF21032
• Sequence:
  MEAEAADAPPGGVESALSCFSFNQDCTSLATGTKAGYKLFSLSSVEQLDQVHGSNEIPDV
  YIVERLFSSSLVVVVSHTKPRQMNVYHFKKGTEICNYSYSSNILSIRLNRQRLLVCLEES
  IYIHNIKDMKLLKTLLDIPANPTGLCALSINHSNSYLAYPGSLTSGEIVLYDGNSLKTVC
  TIAAHEGTLAAITFNASGSKLASASEKGTVIRVFSVPDGQKLYEFRRGMKRYVTISSLVF
  SMDSQFLCASSNTETVHIFKLEQVTNSRPEEPSTWSGYMGKMFMAATNYLPTQVSDMMHQ
  DRAFATARLNFSGQRNICTLSTIQKLPRLLVASSSGHLYMYNLDPQDGGECVLIKTHSLL
  GSGTTEENKENDLRPSLPQSYAATVARPSASSASTVPGYSEDGGALRGEVIPEHEFATGP
  VCLDDENEFPPIILCRGNQKGKTKQS
• Function: Component of the autophagy machinery that controls the major intracellular degradation process by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation. Plays an important role in starvation- and calcium-mediated autophagy, as well as in mitophagy. Functions downstream of the ULK1 and PI3-kinases that produce phosphatidylinositol 3-phosphate (PtdIns3P) on membranes of the endoplasmic reticulum once activated. Binds phosphatidylinositol 3-phosphate (PtdIns3P), and maybe other phosphoinositides including PtdIns3,5P2 and PtdIns5P, and is recruited to phagophore assembly sites at the endoplasmic reticulum membranes. There, it assists WIPI2 in the recruitment of ATG12-ATG5-ATG16L1, a complex that directly controls the elongation of the nascent autophagosomal membrane. Together with WDR45/WIPI4, promotes ATG2 (ATG2A or ATG2B)-mediated lipid transfer by enhancing ATG2-association with phosphatidylinositol 3-monophosphate (PI3P)-containing membranes. Involved in xenophagy of Staphylococcus aureus. Invading S.aureus cells become entrapped in autophagosome-like WIPI1 positive vesicles targeted for lysosomal degradation. Also plays a distinct role in controlling the transcription of melanogenic enzymes and melanosome maturation, a process that is distinct from starvation-induced autophagy. May also regulate the trafficking of proteins involved in the mannose-6-phosphate receptor (MPR) recycling pathway.
• Tissue Specificity: Ubiquitously expressed. Highly expressed in skeletal muscle, heart, testis, pancreas and placenta. Highly expressed in G361, Sk-mel-28, Sk-mel-13, WM852 and WM451 cells. Up-regulated in a variety of tumor tissues.
• KEGG Pathway:
  Autophagy - other (hsa04136)
  Autophagy - animal (hsa04140)
  Alzheimer disease (hsa05010)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Shigellosis (hsa05131)
• Reactome Pathway:
  XBP1(S) activates chaperone genes (R-HSA-381038)
  Macroautophagy (R-HSA-1632852)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	WD repeat domain phosphoinositide-interacting protein 1 affects the response to substance of Etoposide.	[21]
Mitomycin	DMH0ZJE	Approved	WD repeat domain phosphoinositide-interacting protein 1 affects the response to substance of Mitomycin.	[21]

36 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 WD repeat domain phosphoinositide-interacting protein 1.	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[5]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of WD repeat domain phosphoinositide-interacting protein 1.	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[8]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[9]
Menadione	DMSJDTY	Approved	Menadione affects the expression of WD repeat domain phosphoinositide-interacting protein 1.	[10]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[11]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[12]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[13]
Haloperidol	DM96SE0	Approved	Haloperidol increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[1]
Fluoxetine	DM3PD2C	Approved	Fluoxetine increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[13]
Sertraline	DM0FB1J	Approved	Sertraline increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[13]
Tetracycline	DMZA017	Approved	Tetracycline increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[1]
Thioridazine	DM35M8J	Approved	Thioridazine increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[13]
Trovafloxacin	DM6AN32	Approved	Trovafloxacin decreases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[14]
Imipramine	DM2NUH3	Approved	Imipramine increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[13]
Clomipramine	DMINRKW	Approved	Clomipramine increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[13]
Erythromycin	DM4K7GQ	Approved	Erythromycin increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[1]
Pentamidine	DMHZJCG	Approved	Pentamidine increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[13]
Flecainide	DMSQDLE	Approved	Flecainide increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[13]
Perhexiline	DMINO7Z	Approved	Perhexiline increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[13]
Procainamide	DMNMXR8	Approved	Procainamide increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[13]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[15]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[13]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[13]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[16]
Chlorcyclizine	DM3L52Q	Phase 1	Chlorcyclizine increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[13]
ZIMELIDINE	DMNI3U2	Withdrawn from market	ZIMELIDINE increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[13]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of WD repeat domain phosphoinositide-interacting protein 1.	[20]

References

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• [4] 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.
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• [6] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [7] 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.
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• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [12] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [13] A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol Sci. 2005 Feb;83(2):282-92.
• [14] TNF enhances trovafloxacin-induced in vitro hepatotoxicity by inhibiting protective autophagy. Toxicol Lett. 2021 May 15;342:73-84. doi: 10.1016/j.toxlet.2021.02.009. Epub 2021 Feb 17.
• [15] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [16] 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.
• [17] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [18] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [21] 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.