Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU4LCJV)

• DOT Name: Bone marrow stromal antigen 2 (BST2)
• Synonyms: BST-2; HM1.24 antigen; Tetherin; CD antigen CD317
• Gene Name: BST2
• UniProt ID: BST2_HUMAN
• PDB ID: 2LK9; 2X7A; 2XG7; 3MQ7; 3MQ9; 3MQB; 3MQC; 3NWH; 4P6Z; 6CM9; 6CRI; 6D83; 6D84; 6DFF; 7Q9A
• Pfam ID: PF16716
• Sequence:
  MASTSYDYCRVPMEDGDKRCKLLLGIGILVLLIIVILGVPLIIFTIKANSEACRDGLRAV
  MECRNVTHLLQQELTEAQKGFQDVEAQAATCNHTVMALMASLDAEKAQGQKKVEELEGEI
  TTLNHKLQDASAEVERLRRENQVLSVRIADKKYYPSSQDSSSAAAPQLLIVLLGLSALLQ
• Function: IFN-induced antiviral host restriction factor which efficiently blocks the release of diverse mammalian enveloped viruses by directly tethering nascent virions to the membranes of infected cells. Acts as a direct physical tether, holding virions to the cell membrane and linking virions to each other. The tethered virions can be internalized by endocytosis and subsequently degraded or they can remain on the cell surface. In either case, their spread as cell-free virions is restricted. Its target viruses belong to diverse families, including retroviridae: human immunodeficiency virus type 1 (HIV-1), human immunodeficiency virus type 2 (HIV-2), simian immunodeficiency viruses (SIVs), equine infectious anemia virus (EIAV), feline immunodeficiency virus (FIV), prototype foamy virus (PFV), Mason-Pfizer monkey virus (MPMV), human T-cell leukemia virus type 1 (HTLV-1), Rous sarcoma virus (RSV) and murine leukemia virus (MLV), flavivirideae: hepatitis C virus (HCV), filoviridae: ebola virus (EBOV) and marburg virus (MARV), arenaviridae: lassa virus (LASV) and machupo virus (MACV), herpesviridae: kaposis sarcoma-associated herpesvirus (KSHV), rhabdoviridae: vesicular stomatitis virus (VSV), orthomyxoviridae: influenza A virus, paramyxoviridae: nipah virus, and coronaviridae: SARS-CoV. Can inhibit cell surface proteolytic activity of MMP14 causing decreased activation of MMP15 which results in inhibition of cell growth and migration. Can stimulate signaling by LILRA4/ILT7 and consequently provide negative feedback to the production of IFN by plasmacytoid dendritic cells in response to viral infection. Plays a role in the organization of the subapical actin cytoskeleton in polarized epithelial cells. Isoform 1 and isoform 2 are both effective viral restriction factors but have differing antiviral and signaling activities. Isoform 2 is resistant to HIV-1 Vpu-mediated degradation and restricts HIV-1 viral budding in the presence of Vpu. Isoform 1 acts as an activator of NF-kappa-B and this activity is inhibited by isoform 2.
• Tissue Specificity: Predominantly expressed in liver, lung, heart and placenta. Lower levels in pancreas, kidney, skeletal muscle and brain. Overexpressed in multiple myeloma cells. Highly expressed during B-cell development, from pro-B precursors to plasma cells. Highly expressed on T-cells, monocytes, NK cells and dendritic cells (at protein level).
• KEGG Pathway:
  Viral life cycle - HIV-1 (hsa03250)
  Herpes simplex virus 1 infection (hsa05168)
  Human immunodeficiency virus 1 infection (hsa05170)
• Reactome Pathway:
  Interferon alpha/beta signaling (R-HSA-909733)
  SARS-CoV-1 activates/modulates innate immune responses (R-HSA-9692916)
  Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Bone marrow stromal antigen 2 (BST2) affects the response to substance of Mitoxantrone.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Bone marrow stromal antigen 2 (BST2).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Bone marrow stromal antigen 2 (BST2).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Bone marrow stromal antigen 2 (BST2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Bone marrow stromal antigen 2 (BST2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Bone marrow stromal antigen 2 (BST2).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Bone marrow stromal antigen 2 (BST2).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Bone marrow stromal antigen 2 (BST2).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Bone marrow stromal antigen 2 (BST2).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Bone marrow stromal antigen 2 (BST2).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Bone marrow stromal antigen 2 (BST2).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of Bone marrow stromal antigen 2 (BST2).	[10]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Bone marrow stromal antigen 2 (BST2).	[11]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Bone marrow stromal antigen 2 (BST2).	[8]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Bone marrow stromal antigen 2 (BST2).	[12]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Bone marrow stromal antigen 2 (BST2).	[8]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of Bone marrow stromal antigen 2 (BST2).	[8]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of Bone marrow stromal antigen 2 (BST2).	[8]
Tofacitinib	DMBS370	Approved	Tofacitinib decreases the expression of Bone marrow stromal antigen 2 (BST2).	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Bone marrow stromal antigen 2 (BST2).	[14]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Bone marrow stromal antigen 2 (BST2).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Bone marrow stromal antigen 2 (BST2).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Bone marrow stromal antigen 2 (BST2).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Bone marrow stromal antigen 2 (BST2).	[18]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Bone marrow stromal antigen 2 (BST2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Bone marrow stromal antigen 2 (BST2).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Bone marrow stromal antigen 2 (BST2).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Bone marrow stromal antigen 2 (BST2).	[21]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Bone marrow stromal antigen 2 (BST2).	[22]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Bone marrow stromal antigen 2 (BST2).	[23]

References

• [1] 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.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Profile of estrogen-responsive genes in an estrogen-specific mammary gland outgrowth model. Mol Reprod Dev. 2009 Aug;76(8):733-50. doi: 10.1002/mrd.21041.
• [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.
• [8] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [9] Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006 Dec 1;66(23):11187-93. doi: 10.1158/0008-5472.CAN-06-1274.
• [10] 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.
• [11] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [12] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [13] White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nat Cell Biol. 2015 Jan;17(1):57-67. doi: 10.1038/ncb3075. Epub 2014 Dec 8.
• [14] Aberrant regulation of the BST2 (Tetherin) promoter enhances cell proliferation and apoptosis evasion in high grade breast cancer cells. PLoS One. 2013 Jun 20;8(6):e67191. doi: 10.1371/journal.pone.0067191. Print 2013.
• [15] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [16] 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.
• [17] BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol. 2012 Dec;92(6):1147-54. doi: 10.1189/jlb.0312165. Epub 2012 Jul 16.
• [18] 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.
• [19] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [20] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [23] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [24] 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.