Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3DIBU3)

• DOT Name: Butyrophilin subfamily 3 member A2 (BTN3A2)
• Gene Name: BTN3A2
• Related Disease:
  Neoplasm
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Hepatitis C virus infection
  Major depressive disorder
  Matthew-Wood syndrome
  Ovarian cancer
  Ovarian neoplasm
  Epithelial ovarian cancer
  Gastric cancer
  Stomach cancer
  Schizophrenia
  Triple negative breast cancer
  Type-1 diabetes
• UniProt ID: BT3A2_HUMAN
• PDB ID: 4F8Q
• Pfam ID: PF07686
• Sequence:
  MKMASSLAFLLLNFHVSLLLVQLLTPCSAQFSVLGPSGPILAMVGEDADLPCHLFPTMSA
  ETMELKWVSSSLRQVVNVYADGKEVEDRQSAPYRGRTSILRDGITAGKAALRIHNVTASD
  SGKYLCYFQDGDFYEKALVELKVAALGSNLHVEVKGYEDGGIHLECRSTGWYPQPQIQWS
  NAKGENIPAVEAPVVADGVGLYEVAASVIMRGGSGEGVSCIIRNSLLGLEKTASISIADP
  FFRSAQPWIAALAGTLPILLLLLAGASYFLWRQQKEITALSSEIESEQEMKEMGYAATER
  EISLRESLQEELKRKKIQYLTRGEESSSDTNKSA
• Function: Plays a role in T-cell responses in the adaptive immune response. Inhibits the release of IFNG from activated T-cells.
• Tissue Specificity: Detected in T-cells and natural killer cells.
• Reactome Pathway: Butyrophilin (BTN) family interactions (R-HSA-8851680)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[5]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[6]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[7]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[3]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[3]
Epithelial ovarian cancer	DIS56MH2	moderate	Biomarker	[3]
Gastric cancer	DISXGOUK	moderate	Biomarker	[8]
Stomach cancer	DISKIJSX	moderate	Biomarker	[8]
Schizophrenia	DISSRV2N	Limited	Biomarker	[9]
Triple negative breast cancer	DISAMG6N	Limited	Biomarker	[3]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[10]

3 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 Butyrophilin subfamily 3 member A2 (BTN3A2).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Butyrophilin subfamily 3 member A2 (BTN3A2).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Butyrophilin subfamily 3 member A2 (BTN3A2).	[26]

15 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 Butyrophilin subfamily 3 member A2 (BTN3A2).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Butyrophilin subfamily 3 member A2 (BTN3A2).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Butyrophilin subfamily 3 member A2 (BTN3A2).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Butyrophilin subfamily 3 member A2 (BTN3A2).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Butyrophilin subfamily 3 member A2 (BTN3A2).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Butyrophilin subfamily 3 member A2 (BTN3A2).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Butyrophilin subfamily 3 member A2 (BTN3A2).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Butyrophilin subfamily 3 member A2 (BTN3A2).	[19]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Butyrophilin subfamily 3 member A2 (BTN3A2).	[20]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Butyrophilin subfamily 3 member A2 (BTN3A2).	[21]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Butyrophilin subfamily 3 member A2 (BTN3A2).	[22]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Butyrophilin subfamily 3 member A2 (BTN3A2).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Butyrophilin subfamily 3 member A2 (BTN3A2).	[24]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Butyrophilin subfamily 3 member A2 (BTN3A2).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Butyrophilin subfamily 3 member A2 (BTN3A2).	[27]

References

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• [3] BTN3A2 serves as a prognostic marker and favors immune infiltration in triple-negative breast cancer.J Cell Biochem. 2020 Mar;121(3):2643-2654. doi: 10.1002/jcb.29485. Epub 2019 Nov 6.
• [4] A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.Nat Genet. 2018 Jul;50(7):968-978. doi: 10.1038/s41588-018-0132-x. Epub 2018 Jun 18.
• [5] Fine-mapping butyrophilin family genes revealed several polymorphisms influencing viral genotype selection in hepatitis C infection.Genes Immun. 2015 Jul-Aug;16(5):297-300. doi: 10.1038/gene.2015.14. Epub 2015 Apr 30.
• [6] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [7] BTN3A is a prognosis marker and a promising target for V9V2 T cells based-immunotherapy in pancreatic ductal adenocarcinoma (PDAC).Oncoimmunology. 2017 Sep 21;7(1):e1372080. doi: 10.1080/2162402X.2017.1372080. eCollection 2017.
• [8] Exome Array Analysis Identifies Variants in SPOCD1 and BTN3A2 That Affect Risk for Gastric Cancer.Gastroenterology. 2017 Jun;152(8):2011-2021. doi: 10.1053/j.gastro.2017.02.017. Epub 2017 Feb 27.
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• [10] Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex.Genes Immun. 2009 Jun;10(4):323-33. doi: 10.1038/gene.2009.13. Epub 2009 Mar 19.
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• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [18] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [19] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [20] 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.
• [21] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [22] Effects of aspirin on metastasis-associated gene expression detected by cDNA microarray. Acta Pharmacol Sin. 2004 Oct;25(10):1327-33.
• [23] 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.
• [24] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [25] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [26] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [27] 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.