Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1BI27E)

• DOT Name: Intercellular adhesion molecule 4 (ICAM4)
• Synonyms: ICAM-4; Landsteiner-Wiener blood group glycoprotein; LW blood group protein; CD antigen CD242
• Gene Name: ICAM4
• Related Disease:
  Tuberculosis
  Breast cancer
  Breast carcinoma
  Hematologic disease
  Prostate cancer
  Prostate carcinoma
  Sickle-cell anaemia
  Systemic lupus erythematosus
  Thrombosis
• UniProt ID: ICAM4_HUMAN
• Pfam ID: PF03921
• Sequence:
  MGSLFPLSLLFFLAAAYPGVGSALGRRTKRAQSPKGSPLAPSGTSVPFWVRMSPEFVAVQ
  PGKSVQLNCSNSCPQPQNSSLRTPLRQGKTLRGPGWVSYQLLDVRAWSSLAHCLVTCAGK
  TRWATSRITAYKPPHSVILEPPVLKGRKYTLRCHVTQVFPVGYLVVTLRHGSRVIYSESL
  ERFTGLDLANVTLTYEFAAGPRDFWQPVICHARLNLDGLVVRNSSAPITLMLAWSPAPTA
  LASGSIAALVGILLTVGAAYLCKCLAMKSQA
• Function: ICAM proteins are ligands for the leukocyte adhesion protein LFA-1 (integrin alpha-L/beta-2). ICAM4 is also a ligand for alpha-4/beta-1 and alpha-V integrins.
• Tissue Specificity: Erythrocytes.
• Reactome Pathway:
  Integrin cell surface interactions (R-HSA-216083)
  Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Tuberculosis	DIS2YIMD	Definitive	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Hematologic disease	DIS9XD9A	Strong	Genetic Variation	[3]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[4]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[4]
Sickle-cell anaemia	DIS5YNZB	Strong	Biomarker	[5]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[6]
Thrombosis	DIS2TXP8	Limited	Biomarker	[7]

1 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 Intercellular adhesion molecule 4 (ICAM4).	[8]

12 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 Intercellular adhesion molecule 4 (ICAM4).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Intercellular adhesion molecule 4 (ICAM4).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Intercellular adhesion molecule 4 (ICAM4).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Intercellular adhesion molecule 4 (ICAM4).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Intercellular adhesion molecule 4 (ICAM4).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Intercellular adhesion molecule 4 (ICAM4).	[13]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Intercellular adhesion molecule 4 (ICAM4).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Intercellular adhesion molecule 4 (ICAM4).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Intercellular adhesion molecule 4 (ICAM4).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Intercellular adhesion molecule 4 (ICAM4).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Intercellular adhesion molecule 4 (ICAM4).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Intercellular adhesion molecule 4 (ICAM4).	[14]

References

• [1] Host ICAMs play a role in cell invasion by Mycobacterium tuberculosis and Plasmodium falciparum.Nat Commun. 2015 Jan 14;6:6049. doi: 10.1038/ncomms7049.
• [2] Role of ICAM1 in invasion of human breast cancer cells.Carcinogenesis. 2005 May;26(5):943-50. doi: 10.1093/carcin/bgi070. Epub 2005 Mar 17.
• [3] Genetic association study of systemic lupus erythematosus and disease subphenotypes in European populations.Clin Rheumatol. 2016 May;35(5):1161-8. doi: 10.1007/s10067-016-3235-8. Epub 2016 Mar 28.
• [4] ICAM gene cluster SNPs and prostate cancer risk in African Americans.Hum Genet. 2006 Aug;120(1):69-76. doi: 10.1007/s00439-006-0184-3. Epub 2006 May 30.
• [5] Valsartan impedes epinephrine-induced ICAM-4 activation on normal, sickle cell trait and sickle cell disease red blood cells.PLoS One. 2019 May 13;14(5):e0216467. doi: 10.1371/journal.pone.0216467. eCollection 2019.
• [6] Variation in the ICAM1-ICAM4-ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries.Ann Rheum Dis. 2012 Nov;71(11):1809-14. doi: 10.1136/annrheumdis-2011-201110. Epub 2012 Apr 20.
• [7] LW protein: a promiscuous integrin receptor activated by adrenergic signaling.Transfus Clin Biol. 2006 Mar-Apr;13(1-2):44-9. doi: 10.1016/j.tracli.2006.02.022. Epub 2006 Mar 29.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [16] 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.
• [17] 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.
• [18] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.