Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCK671N)

• DOT Name: Oxysterol-binding protein-related protein 2 (OSBPL2)
• Synonyms: ORP-2; OSBP-related protein 2
• Gene Name: OSBPL2
• Related Disease:
  Autosomal dominant nonsyndromic hearing loss 67
  Nonsyndromic genetic hearing loss
  Autosomal dominant nonsyndromic hearing loss
• UniProt ID: OSBL2_HUMAN
• PDB ID: 5ZM8
• Pfam ID: PF01237
• Sequence:
  MNGEEEFFDAVTGFDSDNSSGEFSEANQKVTGMIDLDTSKNNRIGKTGERPSQENGIQKH
  RTSLPAPMFSRSDFSVWTILKKCVGLELSKITMPIAFNEPLSFLQRITEYMEHVYLIHRA
  SCQPQPLERMQSVAAFAVSAVASQWERTGKPFNPLLGETYELIREDLGFRFISEQVSHHP
  PISAFHSEGLNHDFLFHGSIYPKLKFWGKSVEAEPRGTITLELLKHNEAYTWTNPTCCVH
  NVIIGKLWIEQYGTVEILNHRTGHKCVLHFKPCGLFGKELHKVEGHIQDKNKKKLFMIYG
  KWTECLWGIDPVSYESFKKQERRGDHLRKAKLDEDSGKADSDVADDVPVAQETVQVIPGS
  KLLWRINTRPPNSAQMYNFTSFTVSLNELETGMEKTLPPTDCRLRPDIRGMENGNMDLAS
  QEKERLEEKQREARRERAKEEAEWQTRWFYPGNNPYTGTPDWLYAGDYFERNFSDCPDIY
• Function: Intracellular transport protein that binds sterols and phospholipids and mediates lipid transport between intracellular compartments. Increases plasma membrane cholesterol levels and decreases phosphatidylinositol-4,5-bisphosphate levels in the cell membrane. Binds phosphoinositides, such as phosphatidylinositol-4,5-bisphosphate. Exhibits strong binding to phosphatidic acid and weak binding to phosphatidylinositol 3-phosphate. Binds cholesterol, dehydroergosterol, 22(R)-hydroxycholesterol and 25-hydroxycholesterol (in vitro).
• Tissue Specificity: Widely expressed.
• Reactome Pathway: Synthesis of bile acids and bile salts (R-HSA-192105)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant nonsyndromic hearing loss 67	DIS6SPZD	Strong	Autosomal dominant	[1]
Nonsyndromic genetic hearing loss	DISZX61P	Moderate	Autosomal dominant	[2]
Autosomal dominant nonsyndromic hearing loss	DISYC1G0	Supportive	Autosomal dominant	[1]

10 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 Oxysterol-binding protein-related protein 2 (OSBPL2).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Oxysterol-binding protein-related protein 2 (OSBPL2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Oxysterol-binding protein-related protein 2 (OSBPL2).	[5]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Oxysterol-binding protein-related protein 2 (OSBPL2).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Oxysterol-binding protein-related protein 2 (OSBPL2).	[5]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Oxysterol-binding protein-related protein 2 (OSBPL2).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Oxysterol-binding protein-related protein 2 (OSBPL2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Oxysterol-binding protein-related protein 2 (OSBPL2).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Oxysterol-binding protein-related protein 2 (OSBPL2).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Oxysterol-binding protein-related protein 2 (OSBPL2).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Oxysterol-binding protein-related protein 2 (OSBPL2).	[11]

References

• [1] Identification of OSBPL2 as a novel candidate gene for progressive nonsyndromic hearing loss by whole-exome sequencing. Genet Med. 2015 Mar;17(3):210-8. doi: 10.1038/gim.2014.90. Epub 2014 Jul 31.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [6] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [7] 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.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [10] 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.
• [11] 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.
• [12] 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.