Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9L72MD)

• DOT Name: Endothelial cell-specific chemotaxis regulator (ECSCR)
• Synonyms: Apoptosis regulator through modulating IAP expression; ARIA; Endothelial cell-specific molecule 2
• Gene Name: ECSCR
• Related Disease:
  Neoplasm
  Non-insulin dependent diabetes
  Type-1/2 diabetes
  Alzheimer disease
  Alzheimer disease 3
  Arteriosclerosis
  Asthma
  Atherosclerosis
  Capillary hemangioma
  Non-small-cell lung cancer
  Rhinitis
  Subarachnoid hemorrhage
• UniProt ID: ECSCR_HUMAN
• Pfam ID: PF15820
• Sequence:
  MGTAGAMQLCWVILGFLLFRGHNSQPTMTQTSSSQGGLGGLSLTTEPVSSNPGYIPSSEA
  NRPSHLSSTGTPGAGVPSSGRDGGTSRDTFQTVPPNSTTMSLSMREDATILPSPTSETVL
  TVAAFGVISFIVILVVVVIILVGVVSLRFKCRKSKESEDPQKPGSSGLSESCSTANGEKD
  SITLISMKNINMNNGKQSLSAEKVL
• Function: Regulates endothelial chemotaxis and tube formation. Has a role in angiogenesis and apoptosis via modulation of the actin cytoskeleton and facilitation of proteasomal degradation of the apoptosis inhibitors BIRC3/IAP1 and BIRC2/IAP2.
• Tissue Specificity: Highest expression in endothelial cells. Also detected in vascular smooth muscle, macrophages, lymphocytes, and mast cells.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[2]
Type-1/2 diabetes	DISIUHAP	Definitive	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[3]
Alzheimer disease 3	DISVT69G	Strong	Altered Expression	[3]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Asthma	DISW9QNS	Strong	Biomarker	[5]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[4]
Capillary hemangioma	DISQ8XPT	Strong	Altered Expression	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[7]
Rhinitis	DISKLMN7	Limited	Biomarker	[5]
Subarachnoid hemorrhage	DISI7I8Y	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Endothelial cell-specific chemotaxis regulator (ECSCR).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Endothelial cell-specific chemotaxis regulator (ECSCR).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Endothelial cell-specific chemotaxis regulator (ECSCR).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Endothelial cell-specific chemotaxis regulator (ECSCR).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Endothelial cell-specific chemotaxis regulator (ECSCR).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Endothelial cell-specific chemotaxis regulator (ECSCR).	[14]

References

• [1] Identification of ARIA regulating endothelial apoptosis and angiogenesis by modulating proteasomal degradation of cIAP-1 and cIAP-2.Proc Natl Acad Sci U S A. 2009 May 19;106(20):8227-32. doi: 10.1073/pnas.0806780106. Epub 2009 May 1.
• [2] Association between area-level socioeconomic status, accessibility and diabetes-related hospitalisations: a cross-sectional analysis of data from Western Victoria, Australia.BMJ Open. 2019 May 22;9(5):e026880. doi: 10.1136/bmjopen-2018-026880.
• [3] Chronic Verubecestat Treatment Suppresses Amyloid Accumulation in Advanced Aged Tg2576-APPswe Mice Without Inducing Microhemorrhage.J Alzheimers Dis. 2017;59(4):1393-1413. doi: 10.3233/JAD-170056.
• [4] Loss of apoptosis regulator through modulating IAP expression (ARIA) protects blood vessels from atherosclerosis.J Biol Chem. 2015 Feb 6;290(6):3784-92. doi: 10.1074/jbc.M114.605287. Epub 2014 Dec 22.
• [5] Guidance to 2018 good practice: ARIA digitally-enabled, integrated, person-centred care for rhinitis and asthma.Clin Transl Allergy. 2019 Mar 11;9:16. doi: 10.1186/s13601-019-0252-0. eCollection 2019.
• [6] Endothelial cell-specific chemotaxis receptor (ECSCR) enhances vascular endothelial growth factor (VEGF) receptor-2/kinase insert domain receptor (KDR) activation and promotes proteolysis of internalized KDR.J Biol Chem. 2013 Apr 12;288(15):10265-74. doi: 10.1074/jbc.M112.413542. Epub 2013 Feb 7.
• [7] Favorable prognosis of operable non-small cell lung cancer (NSCLC) patients harboring an increased expression of tumor endothelial markers (TEMs).Lung Cancer. 2013 Aug;81(2):252-8. doi: 10.1016/j.lungcan.2013.04.014. Epub 2013 May 10.
• [8] Cerebral amyloid angiopathy-related atraumatic convexal subarachnoid hemorrhage: an ARIA before the tsunami.J Cereb Blood Flow Metab. 2015 May;35(5):710-7. doi: 10.1038/jcbfm.2015.25. Epub 2015 Mar 4.
• [9] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [10] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [14] 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.