Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLDZ0KZ)

• DOT Name: Leukocyte surface antigen CD47 (CD47)
• Synonyms: Antigenic surface determinant protein OA3; Integrin-associated protein; IAP; Protein MER6; CD antigen CD47
• Gene Name: CD47
• UniProt ID: CD47_HUMAN
• PDB ID: 2JJS; 2JJT; 2VSC; 4CMM; 4KJY; 5IWL; 5TZ2; 5TZT; 5TZU; 7MYZ; 7WN8; 7XJF; 7YGG
• Pfam ID: PF04549 ; PF08204
• Sequence:
  MWPLVAALLLGSACCGSAQLLFNKTKSVEFTFCNDTVVIPCFVTNMEAQNTTEVYVKWKF
  KGRDIYTFDGALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT
  REGETIIELKYRVVSWFSPNENILIVIFPIFAILLFWGQFGIKTLKYRSGGMDEKTIALL
  VAGLVITVIVIVGAILFVPGEYSLKNATGLGLIVTSTGILILLHYYVFSTAIGLTSFVIA
  ILVIQVIAYILAVVGLSLCIAACIPMHGPLLISGLSILALAQLLGLVYMKFVASNQKTIQ
  PPRKAVEEPLNAFKESKGMMNDE
• Function: Adhesive protein that mediates cell-to-cell interactions. Acts as a receptor for thrombospondin THBS1 and as modulator of integrin signaling through the activation of heterotrimeric G proteins. Involved in signal transduction, cardiovascular homeostasis, inflammation, apoptosis, angiogenesis, cellular self-renewal, and immunoregulation. Plays a role in modulating pulmonary endothelin EDN1 signaling. Modulates nitrous oxide (NO) signaling, in response to THBS1, hence playing a role as a pressor agent, supporting blood pressure. Plays an important role in memory formation and synaptic plasticity in the hippocampus. Receptor for SIRPA, binding to which prevents maturation of immature dendritic cells and inhibits cytokine production by mature dendritic cells. Interaction with SIRPG mediates cell-cell adhesion, enhances superantigen-dependent T-cell-mediated proliferation and costimulates T-cell activation. Positively modulates FAS-dependent apoptosis in T-cells, perhaps by enhancing FAS clustering. Plays a role in suppressing angiogenesis and may be involved in metabolic dysregulation during normal aging. In response to THBS1, negatively modulates wound healing. Inhibits stem cell self-renewal, in response to THBS1, probably by regulation of the stem cell transcription factors POU5F1/OCT4, SOX2, MYC/c-Myc and KLF4. May play a role in membrane transport and/or integrin dependent signal transduction. May prevent premature elimination of red blood cells.
• Tissue Specificity: Very broadly distributed on normal adult tissues, as well as ovarian tumors, being especially abundant in some epithelia and the brain.
• KEGG Pathway:
  Efferocytosis (hsa04148)
  ECM-receptor interaction (hsa04512)
• Reactome Pathway:
  Integrin cell surface interactions (R-HSA-216083)
  Signal regulatory protein family interactions (R-HSA-391160)
  Neutrophil degranulation (R-HSA-6798695)
  Cell surface interactions at the vascular wall (R-HSA-202733)

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
Paclitaxel	DMLB81S	Approved	Leukocyte surface antigen CD47 (CD47) decreases the response to substance of Paclitaxel.	[21]

1 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 Leukocyte surface antigen CD47 (CD47).	[1]

19 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 Leukocyte surface antigen CD47 (CD47).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Leukocyte surface antigen CD47 (CD47).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Leukocyte surface antigen CD47 (CD47).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Leukocyte surface antigen CD47 (CD47).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Leukocyte surface antigen CD47 (CD47).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Leukocyte surface antigen CD47 (CD47).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Leukocyte surface antigen CD47 (CD47).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Leukocyte surface antigen CD47 (CD47).	[9]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Leukocyte surface antigen CD47 (CD47).	[10]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Leukocyte surface antigen CD47 (CD47).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Leukocyte surface antigen CD47 (CD47).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Leukocyte surface antigen CD47 (CD47).	[13]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Leukocyte surface antigen CD47 (CD47).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Leukocyte surface antigen CD47 (CD47).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Leukocyte surface antigen CD47 (CD47).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Leukocyte surface antigen CD47 (CD47).	[17]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Leukocyte surface antigen CD47 (CD47).	[18]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Leukocyte surface antigen CD47 (CD47).	[19]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Leukocyte surface antigen CD47 (CD47).	[20]

References

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• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [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] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] 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.
• [8] 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.
• [9] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [10] Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. Front Physiol. 2016 Nov 24;7:559. doi: 10.3389/fphys.2016.00559. eCollection 2016.
• [11] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [12] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [13] 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.
• [14] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [15] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [16] 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.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [19] [The Role of TSP-1-CD47 in ROS-mediated Pulmonary Fibrosis Induced by Paraquat]. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2018 Sep 20;36(9):653-661. doi: 10.3760/cma.j.issn.1001-9391.2018.09.003.
• [20] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [21] cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance. Breast Cancer Res Treat. 2006 Mar;96(1):17-39. doi: 10.1007/s10549-005-9026-6. Epub 2005 Dec 2.