Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRBLP0R)

• DOT Name: T-cell surface glycoprotein CD3 delta chain (CD3D)
• Synonyms: T-cell receptor T3 delta chain; CD antigen CD3d
• Gene Name: CD3D
• Related Disease:
  Advanced cancer
  Crohn disease
  Immunodeficiency 19
  Adult T-cell leukemia/lymphoma
  Allergic contact dermatitis
  Breast cancer
  Breast carcinoma
  Malignant soft tissue neoplasm
  Melanoma
  Metastatic malignant neoplasm
  Omenn syndrome
  Primary biliary cholangitis
  Sarcoma
  Severe combined immunodeficiency
  T-cell leukaemia
  Adult glioblastoma
  Glioblastoma multiforme
  Type-1 diabetes
  T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta
  Neoplasm
• UniProt ID: CD3D_HUMAN
• PDB ID: 1XIW; 6JXR; 7FJD; 7FJE; 7FJF; 7PHR; 8ES7; 8ES8; 8ES9
• Pfam ID: PF16680 ; PF02189
• Sequence:
  MEHSTFLSGLVLATLLSQVSPFKIPIEELEDRVFVNCNTSITWVEGTVGTLLSDITRLDL
  GKRILDPRGIYRCNGTDIYKDKESTVQVHYRMCQSCVELDPATVAGIIVTDVIATLLLAL
  GVFCFAGHETGRLSGAADTQALLRNDQVYQPLRDRDDAQYSHLGGNWARNK
• Function: Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response. When antigen presenting cells (APCs) activate T-cell receptor (TCR), TCR-mediated signals are transmitted across the cell membrane by the CD3 chains CD3D, CD3E, CD3G and CD3Z. All CD3 chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic domain. Upon TCR engagement, these motifs become phosphorylated by Src family protein tyrosine kinases LCK and FYN, resulting in the activation of downstream signaling pathways. In addition of this role of signal transduction in T-cell activation, CD3D plays an essential role in thymocyte differentiation. Indeed, participates in correct intracellular TCR-CD3 complex assembly and surface expression. In absence of a functional TCR-CD3 complex, thymocytes are unable to differentiate properly. Interacts with CD4 and CD8 and thus serves to establish a functional link between the TCR and coreceptors CD4 and CD8, which is needed for activation and positive selection of CD4 or CD8 T-cells.
• Tissue Specificity: CD3D is mostly present on T-lymphocytes with its TCR-CD3 partners. Present also in fetal NK-cells.
• KEGG Pathway:
  Hematopoietic cell lineage (hsa04640)
  Th1 and Th2 cell differentiation (hsa04658)
  Th17 cell differentiation (hsa04659)
  T cell receptor sig.ling pathway (hsa04660)
  Chagas disease (hsa05142)
  Measles (hsa05162)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
  Primary immunodeficiency (hsa05340)
• Reactome Pathway:
  Downstream TCR signaling (R-HSA-202424)
  Phosphorylation of CD3 and TCR zeta chains (R-HSA-202427)
  Translocation of ZAP-70 to Immunological synapse (R-HSA-202430)
  Generation of second messenger molecules (R-HSA-202433)
  PD-1 signaling (R-HSA-389948)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Crohn disease	DIS2C5Q8	Definitive	Altered Expression	[2]
Immunodeficiency 19	DISLFNN7	Definitive	Autosomal recessive	[3]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Altered Expression	[4]
Allergic contact dermatitis	DISFFVF9	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Altered Expression	[7]
Melanoma	DIS1RRCY	Strong	Biomarker	[8]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[8]
Omenn syndrome	DIS2C887	Strong	Biomarker	[9]
Primary biliary cholangitis	DIS43E0O	Strong	Biomarker	[10]
Sarcoma	DISZDG3U	Strong	Altered Expression	[7]
Severe combined immunodeficiency	DIS6MF4Q	Strong	Genetic Variation	[11]
T-cell leukaemia	DISJ6YIF	Strong	Altered Expression	[4]
Adult glioblastoma	DISVP4LU	moderate	Altered Expression	[12]
Glioblastoma multiforme	DISK8246	moderate	Altered Expression	[12]
Type-1 diabetes	DIS7HLUB	moderate	Biomarker	[13]
T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta	DISPUD3N	Supportive	Autosomal recessive	[14]
Neoplasm	DISZKGEW	Limited	Biomarker	[15]

2 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 T-cell surface glycoprotein CD3 delta chain (CD3D).	[16]
Marinol	DM70IK5	Approved	Marinol increases the methylation of T-cell surface glycoprotein CD3 delta chain (CD3D).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of T-cell surface glycoprotein CD3 delta chain (CD3D).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of T-cell surface glycoprotein CD3 delta chain (CD3D).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of T-cell surface glycoprotein CD3 delta chain (CD3D).	[19]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of T-cell surface glycoprotein CD3 delta chain (CD3D).	[20]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of T-cell surface glycoprotein CD3 delta chain (CD3D).	[22]
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the expression of T-cell surface glycoprotein CD3 delta chain (CD3D).	[23]
Nabiximols	DMHKJ5I	Phase 3	Nabiximols increases the expression of T-cell surface glycoprotein CD3 delta chain (CD3D).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of T-cell surface glycoprotein CD3 delta chain (CD3D).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of T-cell surface glycoprotein CD3 delta chain (CD3D).	[26]

References

• [1] Pathways- and epigenetic-based assessment of relative immune infiltration in various types of solid tumors.Adv Cancer Res. 2019;142:107-143. doi: 10.1016/bs.acr.2019.01.003. Epub 2019 Mar 6.
• [2] NOD2 status and human ileal gene expression.Inflamm Bowel Dis. 2010 Oct;16(10):1649-57. doi: 10.1002/ibd.21208.
• [3] 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.
• [4] Discordant gene and surface expression of the T-cell receptor/CD3 complex in adult T-cell leukemia cells.Cancer Res. 1991 Nov 15;51(22):6084-8.
• [5] Gene expression time course in the human skin during elicitation of allergic contact dermatitis.J Invest Dermatol. 2007 Nov;127(11):2585-95. doi: 10.1038/sj.jid.5700902. Epub 2007 Jun 28.
• [6] Aberrant DNA methylation impacts gene expression and prognosis in breast cancer subtypes.Int J Cancer. 2016 Jan 1;138(1):87-97. doi: 10.1002/ijc.29684. Epub 2015 Jul 30.
• [7] A systematic analysis of immune genes and overall survival in cancer patients.BMC Cancer. 2019 Dec 16;19(1):1225. doi: 10.1186/s12885-019-6414-6.
• [8] The pattern of cytokine gene expression in freshly excised human metastatic melanoma suggests a state of reversible anergy of tumor-infiltrating lymphocytes.Int J Cancer. 1994 May 15;57(4):612-9. doi: 10.1002/ijc.2910570428.
• [9] Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3. J Clin Invest. 2004 Nov;114(10):1512-7. doi: 10.1172/JCI22588.
• [10] Gene expression profiling of early primary biliary cirrhosis: possible insights into the mechanism of action of ursodeoxycholic acid. Liver Int. 2008 Aug;28(7):997-1010. doi: 10.1111/j.1478-3231.2008.01744.x. Epub 2008 Apr 15.
• [11] The respiratory presentation of severe combined immunodeficiency in two Mennonite children at a tertiary centre highlighting the importance of recognizing this pediatric emergency.Can Respir J. 2014 Jan-Feb;21(1):17-9. doi: 10.1155/2014/404506. Epub 2013 Nov 28.
• [12] Tumor image-derived texture features are associated with CD3 T-cell infiltration status in glioblastoma.Oncotarget. 2017 Sep 5;8(60):101244-101254. doi: 10.18632/oncotarget.20643. eCollection 2017 Nov 24.
• [13] Non-HLA genetic factors and insulin dependent diabetes mellitus in the Japanese: TCRA, TCRB and TCRG, INS, THY1, CD3D and ETS1.Dis Markers. 1990 Sep-Oct;8(5):283-94.
• [14] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [15] Paragangliomas of the head and neck region show complete loss of heterozygosity at 11q22-q23 in chief cells and the flow-sorted DNA aneuploid fraction.Hum Pathol. 1998 Oct;29(10):1045-9. doi: 10.1016/s0046-8177(98)90411-7.
• [16] 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.
• [17] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [18] 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.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [21] Epigenetic activation of O-linked -N-acetylglucosamine transferase overrides the differentiation blockage in acute leukemia. EBioMedicine. 2020 Apr;54:102678. doi: 10.1016/j.ebiom.2020.102678. Epub 2020 Apr 6.
• [22] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [23] CDK5-mediated tau accumulation triggers methamphetamine-induced neuronal apoptosis via endoplasmic reticulum-associated degradation pathway. Toxicol Lett. 2018 Aug;292:97-107. doi: 10.1016/j.toxlet.2018.04.027. Epub 2018 Apr 26.
• [24] Clinical response to Nabiximols correlates with the downregulation of immune pathways in multiple sclerosis. Eur J Neurol. 2018 Jul;25(7):934-e70. doi: 10.1111/ene.13623. Epub 2018 Apr 16.
• [25] 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.
• [26] 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.