Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7R0OQQ)

• DOT Name: Oxysterol-binding protein 1 (OSBP)
• Gene Name: OSBP
• Related Disease:
  Mycoses
  Advanced cancer
  Amyotrophic lateral sclerosis type 8
  Arteriosclerosis
  Atherosclerosis
  Cholangiocarcinoma
  Enterovirus infection
  Hyperlipidemia, familial combined, LPL related
  Metastatic malignant neoplasm
  Neoplasm
  Pancreatic cancer
  Cervical carcinoma
  Liposarcoma
  Amyotrophic lateral sclerosis
• UniProt ID: OSBP1_HUMAN
• PDB ID: 2RR3; 7V62
• Pfam ID: PF01237 ; PF00169
• Sequence:
  MAATELRGVVGPGPAAIAALGGGGAGPPVVGGGGGRGDAGPGSGAASGTVVAAAAGGPGP
  GAGGVAAAGPAPAPPTGGSGGSGAGGSGSAREGWLFKWTNYIKGYQRRWFVLSNGLLSYY
  RSKAEMRHTCRGTINLATANITVEDSCNFIISNGGAQTYHLKASSEVERQRWVTALELAK
  AKAVKMLAESDESGDEESVSQTDKTELQNTLRTLSSKVEDLSTCNDLIAKHGTALQRSLS
  ELESLKLPAESNEKIKQVNERATLFRITSNAMINACRDFLMLAQTHSKKWQKSLQYERDQ
  RIRLEETLEQLAKQHNHLERAFRGATVLPANTPGNVGSGKDQCCSGKGDMSDEDDENEFF
  DAPEIITMPENLGHKRTGSNISGASSDISLDEQYKHQLEETKKEKRTRIPYKPNYSLNLW
  SIMKNCIGKELSKIPMPVNFNEPLSMLQRLTEDLEYHELLDRAAKCENSLEQLCYVAAFT
  VSSYSTTVFRTSKPFNPLLGETFELDRLEENGYRSLCEQVSHHPPAAAHHAESKNGWTLR
  QEIKITSKFRGKYLSIMPLGTIHCIFHATGHHYTWKKVTTTVHNIIVGKLWIDQSGEIDI
  VNHKTGDKCNLKFVPYSYFSRDVARKVTGEVTDPSGKVHFALLGTWDEKMECFKVQPVIG
  ENGGDARQRGHEAEESRVMLWKRNPLPKNAENMYYFSELALTLNAWESGTAPTDSRLRPD
  QRLMENGRWDEANAEKQRLEEKQRLSRKKREAEAMKATEDGTPYDPYKALWFERKKDPVT
  KELTHIYRGEYWECKEKQDWSSCPDIF
• Function: Lipid transporter involved in lipid countertransport between the Golgi complex and membranes of the endoplasmic reticulum: specifically exchanges sterol with phosphatidylinositol 4-phosphate (PI4P), delivering sterol to the Golgi in exchange for PI4P, which is degraded by the SAC1/SACM1L phosphatase in the endoplasmic reticulum. Binds cholesterol and a range of oxysterols including 25-hydroxycholesterol. Cholesterol binding promotes the formation of a complex with PP2A and a tyrosine phosphatase which dephosphorylates ERK1/2, whereas 25-hydroxycholesterol causes its disassembly. Regulates cholesterol efflux by decreasing ABCA1 stability.
• Tissue Specificity: Widely expressed.
• Reactome Pathway:
  Synthesis of bile acids and bile salts (R-HSA-192105)
  Sphingolipid de novo biosynthesis (R-HSA-1660661)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mycoses	DIS9K7PB	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Amyotrophic lateral sclerosis type 8	DISA3XPU	Strong	Biomarker	[3]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[4]
Cholangiocarcinoma	DIS71F6X	Strong	Altered Expression	[5]
Enterovirus infection	DISH2UDP	Strong	Biomarker	[6]
Hyperlipidemia, familial combined, LPL related	DISL1CE3	Strong	Genetic Variation	[7]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[9]
Cervical carcinoma	DIST4S00	moderate	Biomarker	[10]
Liposarcoma	DIS8IZVM	moderate	Biomarker	[11]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Oxysterol-binding protein 1 (OSBP).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Oxysterol-binding protein 1 (OSBP).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Oxysterol-binding protein 1 (OSBP).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Oxysterol-binding protein 1 (OSBP).	[20]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Oxysterol-binding protein 1 (OSBP).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Oxysterol-binding protein 1 (OSBP).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Oxysterol-binding protein 1 (OSBP).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Oxysterol-binding protein 1 (OSBP).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Oxysterol-binding protein 1 (OSBP).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Oxysterol-binding protein 1 (OSBP).	[18]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Oxysterol-binding protein 1 (OSBP).	[21]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Oxysterol-binding protein 1 (OSBP).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Oxysterol-binding protein 1 (OSBP).	[23]

References

• [1] The anti-fungal -sitosterol targets the yeast oxysterol-binding protein Osh4.Pest Manag Sci. 2020 Feb;76(2):704-711. doi: 10.1002/ps.5568. Epub 2019 Aug 31.
• [2] The Oxysterol-Binding Protein Cycle: Burning Off PI(4)P to Transport Cholesterol.Annu Rev Biochem. 2018 Jun 20;87:809-837. doi: 10.1146/annurev-biochem-061516-044924. Epub 2018 Mar 29.
• [3] The amyotrophic lateral sclerosis 8 protein, VAP, is required for ER protein quality control.Hum Mol Genet. 2014 Apr 15;23(8):1975-89. doi: 10.1093/hmg/ddt594. Epub 2013 Nov 23.
• [4] Expression of human OSBP-related protein 1L in macrophages enhances atherosclerotic lesion development in LDL receptor-deficient mice.Arterioscler Thromb Vasc Biol. 2007 Jul;27(7):1618-24. doi: 10.1161/ATVBAHA.107.144121. Epub 2007 May 3.
• [5] Expression of oxysterol binding protein isoforms in opisthorchiasis-associated cholangiocarcinoma: a potential molecular marker for tumor metastasis.Parasitol Int. 2012 Mar;61(1):136-9. doi: 10.1016/j.parint.2011.07.003. Epub 2011 Jul 8.
• [6] Poliovirus Evolution toward Independence from the Phosphatidylinositol-4 Kinase III /Oxysterol-Binding Protein Family I Pathway.ACS Infect Dis. 2019 Jun 14;5(6):962-973. doi: 10.1021/acsinfecdis.9b00038. Epub 2019 Apr 5.
• [7] OSBPL10, a novel candidate gene for high triglyceride trait in dyslipidemic Finnish subjects, regulates cellular lipid metabolism.J Mol Med (Berl). 2009 Aug;87(8):825-35. doi: 10.1007/s00109-009-0490-z. Epub 2009 Jun 25.
• [8] Delivery of Constitutively Active Mutant MKK6(E) With TAT-OSBP Induces Apoptosis in Human Ovarian Carcinoma HO8910 Cells.Int J Gynecol Cancer. 2015 Nov;25(9):1548-56. doi: 10.1097/IGC.0000000000000538.
• [9] The role of oxysterol binding protein-related protein 5 in pancreatic cancer.Cancer Sci. 2010 Apr;101(4):898-905. doi: 10.1111/j.1349-7006.2009.01475.x. Epub 2009 Dec 16.
• [10] Oxysterol-binding protein-related protein 4L promotes cell proliferation by sustaining intracellular Ca2+ homeostasis in cervical carcinoma cell lines.Oncotarget. 2016 Oct 4;7(40):65849-65861. doi: 10.18632/oncotarget.11671.
• [11] SBF-1 preferentially inhibits growth of highly malignant human liposarcoma cells.J Pharmacol Sci. 2018 Dec;138(4):271-278. doi: 10.1016/j.jphs.2018.10.009. Epub 2018 Oct 24.
• [12] Oxysterol-binding protein ORP3 rescues the Amyotrophic Lateral Sclerosis-linked mutant VAPB phenotype.Exp Cell Res. 2016 Feb 1;341(1):18-31. doi: 10.1016/j.yexcr.2016.01.013. Epub 2016 Jan 23.
• [13] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [14] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [15] 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.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] 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.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] 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.
• [20] 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.
• [21] Global expression profiling of theophylline response genes in macrophages: evidence of airway anti-inflammatory regulation. Respir Res. 2005 Aug 8;6(1):89. doi: 10.1186/1465-9921-6-89.
• [22] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [23] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [24] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.