Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFJ9FQW)

• DOT Name: Roundabout homolog 2 (ROBO2)
• Gene Name: ROBO2
• Related Disease:
  Congenital anomaly of kidney and urinary tract
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Autism
  Colorectal carcinoma
  Dyschromatosis symmetrica hereditaria
  Major depressive disorder
  Matthew-Wood syndrome
  Myelodysplastic syndrome
  Prostate cancer
  Prostate neoplasm
  Renal hypoplasia
  Vesicoureteral reflux 2
  Cervical carcinoma
  Cervical Intraepithelial neoplasia
  Gastric cancer
  Stomach cancer
  Familial vesicoureteral reflux
  Cholangiocarcinoma
  Chronic obstructive pulmonary disease
  Conduct disorder
  Intrahepatic cholangiocarcinoma
  Neoplasm
  Neuroblastoma
  Prostate carcinoma
  Vesicoureteral reflux
• UniProt ID: ROBO2_HUMAN
• PDB ID: 1UEM; 1UJT; 2EDJ; 5NOI; 6I9S; 6IAA
• Pfam ID: PF00041 ; PF07679 ; PF13927
• Sequence:
  MSLLMFTQLLLCGFLYVRVDGSRLRQEDFPPRIVEHPSDVIVSKGEPTTLNCKAEGRPTP
  TIEWYKDGERVETDKDDPRSHRMLLPSGSLFFLRIVHGRRSKPDEGSYVCVARNYLGEAV
  SRNASLEVALLRDDFRQNPTDVVVAAGEPAILECQPPRGHPEPTIYWKKDKVRIDDKEER
  ISIRGGKLMISNTRKSDAGMYTCVGTNMVGERDSDPAELTVFERPTFLRRPINQVVLEEE
  AVEFRCQVQGDPQPTVRWKKDDADLPRGRYDIKDDYTLRIKKTMSTDEGTYMCIAENRVG
  KMEASATLTVRAPPQFVVRPRDQIVAQGRTVTFPCETKGNPQPAVFWQKEGSQNLLFPNQ
  PQQPNSRCSVSPTGDLTITNIQRSDAGYYICQALTVAGSILAKAQLEVTDVLTDRPPPII
  LQGPANQTLAVDGTALLKCKATGDPLPVISWLKEGFTFPGRDPRATIQEQGTLQIKNLRI
  SDTGTYTCVATSSSGETSWSAVLDVTESGATISKNYDLSDLPGPPSKPQVTDVTKNSVTL
  SWQPGTPGTLPASAYIIEAFSQSVSNSWQTVANHVKTTLYTVRGLRPNTIYLFMVRAINP
  QGLSDPSPMSDPVRTQDISPPAQGVDHRQVQKELGDVLVRLHNPVVLTPTTVQVTWTVDR
  QPQFIQGYRVMYRQTSGLQATSSWQNLDAKVPTERSAVLVNLKKGVTYEIKVRPYFNEFQ
  GMDSESKTVRTTEEAPSAPPQSVTVLTVGSYNSTSISVSWDPPPPDHQNGIIQEYKIWCL
  GNETRFHINKTVDAAIRSVIIGGLFPGIQYRVEVAASTSAGVGVKSEPQPIIIGRRNEVV
  ITENNNSITEQITDVVKQPAFIAGIGGACWVILMGFSIWLYWRRKKRKGLSNYAVTFQRG
  DGGLMSNGSRPGLLNAGDPSYPWLADSWPATSLPVNNSNSGPNEIGNFGRGDVLPPVPGQ
  GDKTATMLSDGAIYSSIDFTTKTSYNSSSQITQATPYATTQILHSNSIHELAVDLPDPQW
  KSSIQQKTDLMGFGYSLPDQNKGNNGGKGGKKKKNKNSSKPQKNNGSTWANVPLPPPPVQ
  PLPGTELEHYAVEQQENGYDSDSWCPPLPVQTYLHQGLEDELEEDDDRVPTPPVRGVASS
  PAISFGQQSTATLTPSPREEMQPMLQAHLDELTRAYQFDIAKQTWHIQSNNQPPQPPVPP
  LGYVSGALISDLETDVADDDADDEEEALEIPRPLRALDQTPGSSMDNLDSSVTGKAFTSS
  QRPRPTSPFSTDSNTSAALSQSQRPRPTKKHKGGRMDQQPALPHRREGMTDEEALVPYSK
  PSFPSPGGHSSSGTASSKGSTGPRKTEVLRAGHQRNASDLLDIGYMGSNSQGQFTGEL
• Function: Receptor for SLIT2, and probably SLIT1, which are thought to act as molecular guidance cue in cellular migration, including axonal navigation at the ventral midline of the neural tube and projection of axons to different regions during neuronal development.
• KEGG Pathway: Axon guidance (hsa04360)
• Reactome Pathway:
  Regulation of commissural axon pathfinding by SLIT and ROBO (R-HSA-428542)
  Regulation of cortical dendrite branching (R-HSA-8985801)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  ROBO receptors bind AKAP5 (R-HSA-9010642)
  Signaling by ROBO receptors (R-HSA-376176)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital anomaly of kidney and urinary tract	DIS84IVH	Definitive	Altered Expression	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[2]
Autism	DISV4V1Z	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[4]
Dyschromatosis symmetrica hereditaria	DIS9HI9T	Strong	Biomarker	[5]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[6]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[7]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[8]
Prostate cancer	DISF190Y	Strong	Biomarker	[9]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[9]
Renal hypoplasia	DISJ5F10	Strong	Genetic Variation	[10]
Vesicoureteral reflux 2	DISBO2ZC	Strong	Autosomal dominant	[11]
Cervical carcinoma	DIST4S00	moderate	Biomarker	[12]
Cervical Intraepithelial neoplasia	DISXP757	moderate	Biomarker	[12]
Gastric cancer	DISXGOUK	moderate	Biomarker	[13]
Stomach cancer	DISKIJSX	moderate	Biomarker	[13]
Familial vesicoureteral reflux	DISUME5E	Supportive	Autosomal dominant	[14]
Cholangiocarcinoma	DIS71F6X	Limited	Biomarker	[15]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Biomarker	[16]
Conduct disorder	DISOLUZ1	Limited	Genetic Variation	[17]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Limited	Biomarker	[15]
Neoplasm	DISZKGEW	Limited	Altered Expression	[18]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[18]
Prostate carcinoma	DISMJPLE	Limited	Genetic Variation	[19]
Vesicoureteral reflux	DISUL6SA	Limited	Genetic Variation	[10]

9 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 Roundabout homolog 2 (ROBO2).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Roundabout homolog 2 (ROBO2).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Roundabout homolog 2 (ROBO2).	[22]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Roundabout homolog 2 (ROBO2).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Roundabout homolog 2 (ROBO2).	[25]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Roundabout homolog 2 (ROBO2).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Roundabout homolog 2 (ROBO2).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Roundabout homolog 2 (ROBO2).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Roundabout homolog 2 (ROBO2).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Roundabout homolog 2 (ROBO2).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Roundabout homolog 2 (ROBO2).	[26]

References

• [1] Intrauterine low-protein diet disturbs metanephric gene expression and induces urinary tract developmental abnormalities in mice.Biochem Biophys Res Commun. 2019 Jun 4;513(3):732-739. doi: 10.1016/j.bbrc.2019.04.057. Epub 2019 Apr 13.
• [2] The Expression of the SLIT-ROBO Family in Adult Patients with Acute Myeloid Leukemia.Arch Immunol Ther Exp (Warsz). 2019 Apr;67(2):109-123. doi: 10.1007/s00005-019-00535-8. Epub 2019 Feb 28.
• [3] Genetic analyses of roundabout (ROBO) axon guidance receptors in autism.Am J Med Genet B Neuropsychiatr Genet. 2008 Oct 5;147B(7):1019-27. doi: 10.1002/ajmg.b.30697.
• [4] Frameshift mutations of axon guidance genes ROBO1 and ROBO2 in gastric and colorectal cancers with microsatellite instability.Pathology. 2013 Dec;45(7):645-50. doi: 10.1097/PAT.0000000000000007.
• [5] Robo and Ror function in a common receptor complex to regulate Wnt-mediated neurite outgrowth in Caenorhabditis elegans.Proc Natl Acad Sci U S A. 2018 Mar 6;115(10):E2254-E2263. doi: 10.1073/pnas.1717468115. Epub 2018 Feb 20.
• [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] ROBO2 is a stroma suppressor gene in the pancreas and acts via TGF- signalling.Nat Commun. 2018 Nov 30;9(1):5083. doi: 10.1038/s41467-018-07497-z.
• [8] Whole-exome and targeted sequencing identify ROBO1 and ROBO2 mutations as progression-related drivers in myelodysplastic syndromes.Nat Commun. 2015 Nov 26;6:8806. doi: 10.1038/ncomms9806.
• [9] Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets.Nat Genet. 2018 May;50(5):682-692. doi: 10.1038/s41588-018-0086-z. Epub 2018 Apr 16.
• [10] ROBO2 gene variants in children with primary nonsyndromic vesicoureteral reflux with or without renal hypoplasia/dysplasia.Pediatr Res. 2016 Jul;80(1):72-6. doi: 10.1038/pr.2016.51. Epub 2016 Mar 22.
• [11] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [12] Inactivation of SLIT2-ROBO1/2 pathway in premalignant lesions of uterine cervix: clinical and prognostic significances.PLoS One. 2012;7(6):e38342. doi: 10.1371/journal.pone.0038342. Epub 2012 Jun 13.
• [13] Correlations between gastric cancer family history and ROBO2 and RASSF2A gene methylations.J Cancer Res Ther. 2016 Apr-Jun;12(2):597-600. doi: 10.4103/0973-1482.146089.
• [14] Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux. Am J Hum Genet. 2007 Apr;80(4):616-32. doi: 10.1086/512735. Epub 2007 Feb 14.
• [15] Exome sequencing of liver fluke-associated cholangiocarcinoma.Nat Genet. 2012 May 6;44(6):690-3. doi: 10.1038/ng.2273.
• [16] Roundabout signaling pathway involved in the pathogenesis of COPD by integrative bioinformatics analysis.Int J Chron Obstruct Pulmon Dis. 2019 Sep 18;14:2145-2162. doi: 10.2147/COPD.S216050. eCollection 2019.
• [17] Replication of a ROBO2 polymorphism associated with conduct problems but not psychopathic tendencies in children.Psychiatr Genet. 2013 Dec;23(6):251-4. doi: 10.1097/YPG.0b013e3283650f83.
• [18] Identification and characterisation of STMN4 and ROBO2 gene involvement in neuroblastoma cell differentiation.Cancer Lett. 2013 Jan 1;328(1):168-75. doi: 10.1016/j.canlet.2012.08.015. Epub 2012 Aug 17.
• [19] Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer.EBioMedicine. 2016 Aug;10:150-63. doi: 10.1016/j.ebiom.2016.07.022. Epub 2016 Jul 20.
• [20] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [21] 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.
• [22] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [23] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [24] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] 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.