Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT52UFVS)

• DOT Name: Roundabout homolog 1 (ROBO1)
• Synonyms: Deleted in U twenty twenty; H-Robo-1
• Gene Name: ROBO1
• Related Disease:
  Neurooculorenal syndrome
  Pituitary hormone deficiency, combined or isolated, 8
  Pituitary stalk interruption syndrome
• UniProt ID: ROBO1_HUMAN
• PDB ID: 2EO9; 2V9Q; 2V9R; 2V9T; 3WIH; 4HLJ; 5O5G; 5O5I; 5OPE; 6A77; 6A78; 6A79
• Pfam ID: PF00041 ; PF07679 ; PF13927
• Sequence:
  MKWKHVPFLVMISLLSLSPNHLFLAQLIPDPEDVERGNDHGTPIPTSDNDDNSLGYTGSR
  LRQEDFPPRIVEHPSDLIVSKGEPATLNCKAEGRPTPTIEWYKGGERVETDKDDPRSHRM
  LLPSGSLFFLRIVHGRKSRPDEGVYVCVARNYLGEAVSHNASLEVAILRDDFRQNPSDVM
  VAVGEPAVMECQPPRGHPEPTISWKKDGSPLDDKDERITIRGGKLMITYTRKSDAGKYVC
  VGTNMVGERESEVAELTVLERPSFVKRPSNLAVTVDDSAEFKCEARGDPVPTVRWRKDDG
  ELPKSRYEIRDDHTLKIRKVTAGDMGSYTCVAENMVGKAEASATLTVQEPPHFVVKPRDQ
  VVALGRTVTFQCEATGNPQPAIFWRREGSQNLLFSYQPPQSSSRFSVSQTGDLTITNVQR
  SDVGYYICQTLNVAGSIITKAYLEVTDVIADRPPPVIRQGPVNQTVAVDGTFVLSCVATG
  SPVPTILWRKDGVLVSTQDSRIKQLENGVLQIRYAKLGDTGRYTCIASTPSGEATWSAYI
  EVQEFGVPVQPPRPTDPNLIPSAPSKPEVTDVSRNTVTLSWQPNLNSGATPTSYIIEAFS
  HASGSSWQTVAENVKTETSAIKGLKPNAIYLFLVRAANAYGISDPSQISDPVKTQDVLPT
  SQGVDHKQVQRELGNAVLHLHNPTVLSSSSIEVHWTVDQQSQYIQGYKILYRPSGANHGE
  SDWLVFEVRTPAKNSVVIPDLRKGVNYEIKARPFFNEFQGADSEIKFAKTLEEAPSAPPQ
  GVTVSKNDGNGTAILVSWQPPPEDTQNGMVQEYKVWCLGNETRYHINKTVDGSTFSVVIP
  FLVPGIRYSVEVAASTGAGSGVKSEPQFIQLDAHGNPVSPEDQVSLAQQISDVVKQPAFI
  AGIGAACWIILMVFSIWLYRHRKKRNGLTSTYAGIRKVPSFTFTPTVTYQRGGEAVSSGG
  RPGLLNISEPAAQPWLADTWPNTGNNHNDCSISCCTAGNGNSDSNLTTYSRPADCIANYN
  NQLDNKQTNLMLPESTVYGDVDLSNKINEMKTFNSPNLKDGRFVNPSGQPTPYATTQLIQ
  SNLSNNMNNGSGDSGEKHWKPLGQQKQEVAPVQYNIVEQNKLNKDYRANDTVPPTIPYNQ
  SYDQNTGGSYNSSDRGSSTSGSQGHKKGARTPKVPKQGGMNWADLLPPPPAHPPPHSNSE
  EYNISVDESYDQEMPCPVPPARMYLQQDELEEEEDERGPTPPVRGAASSPAAVSYSHQST
  ATLTPSPQEELQPMLQDCPEETGHMQHQPDRRRQPVSPPPPPRPISPPHTYGYISGPLVS
  DMDTDAPEEEEDEADMEVAKMQTRRLLLRGLEQTPASSVGDLESSVTGSMINGWGSASEE
  DNISSGRSSVSSSDGSFFTDADFAQAVAAAAEYAGLKVARRQMQDAAGRRHFHASQCPRP
  TSPVSTDSNMSAAVMQKTRPAKKLKHQPGHLRRETYTDDLPPPPVPPPAIKSPTAQSKTQ
  LEVRPVVVPKLPSMDARTDRSSDRKGSSYKGREVLDGRQVVDMRTNPGDPREAQEQQNDG
  KGRGNKAAKRDLPPAKTHLIQEDILPYCRPTFPTSNNPRDPSSSSSMSSRGSGSRQREQA
  NVGRRNIAEMQVLGGYERGEDNNEELEETES
• Function: Receptor for SLIT1 and SLIT2 that mediates cellular responses to molecular guidance cues in cellular migration, including axonal navigation at the ventral midline of the neural tube and projection of axons to different regions during neuronal development. Interaction with the intracellular domain of FLRT3 mediates axon attraction towards cells expressing NTN1. In axon growth cones, the silencing of the attractive effect of NTN1 by SLIT2 may require the formation of a ROBO1-DCC complex. Plays a role in the regulation of cell migration via its interaction with MYO9B; inhibits MYO9B-mediated stimulation of RHOA GTPase activity, and thereby leads to increased levels of active, GTP-bound RHOA. May be required for lung development.
• Tissue Specificity: Widely expressed, with exception of kidney.
• KEGG Pathway: Axon guidance (hsa04360)
• Reactome Pathway:
  Signaling by ROBO receptors (R-HSA-376176)
  Activation of RAC1 (R-HSA-428540)
  Regulation of commissural axon pathfinding by SLIT and ROBO (R-HSA-428542)
  Inactivation of CDC42 and RAC1 (R-HSA-428543)
  Role of ABL in ROBO-SLIT signaling (R-HSA-428890)
  SLIT2 (R-HSA-8985586)
  Regulation of cortical dendrite branching (R-HSA-8985801)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Netrin-1 signaling (R-HSA-373752)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurooculorenal syndrome	DISAGT5T	Definitive	Autosomal recessive	[1]
Pituitary hormone deficiency, combined or isolated, 8	DIS7D9VT	Strong	Autosomal dominant	[2]
Pituitary stalk interruption syndrome	DISGSN5T	Supportive	Autosomal dominant	[3]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Roundabout homolog 1 (ROBO1) affects the response to substance of Etoposide.	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Roundabout homolog 1 (ROBO1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Roundabout homolog 1 (ROBO1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Roundabout homolog 1 (ROBO1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Roundabout homolog 1 (ROBO1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Roundabout homolog 1 (ROBO1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Roundabout homolog 1 (ROBO1).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Roundabout homolog 1 (ROBO1).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Roundabout homolog 1 (ROBO1).	[12]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Roundabout homolog 1 (ROBO1).	[14]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Roundabout homolog 1 (ROBO1).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Roundabout homolog 1 (ROBO1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Roundabout homolog 1 (ROBO1).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Roundabout homolog 1 (ROBO1).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Roundabout homolog 1 (ROBO1).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Roundabout homolog 1 (ROBO1).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Roundabout homolog 1 (ROBO1).	[23]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Roundabout homolog 1 (ROBO1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Roundabout homolog 1 (ROBO1).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine affects the methylation of Roundabout homolog 1 (ROBO1).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Roundabout homolog 1 (ROBO1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Roundabout homolog 1 (ROBO1).	[22]

References

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• [2] Robo1 regulates the development of major axon tracts and interneuron migration in the forebrain. Development. 2006 Jun;133(11):2243-52. doi: 10.1242/dev.02379.
• [3] Mutations in the Human ROBO1 Gene in Pituitary Stalk Interruption Syndrome. J Clin Endocrinol Metab. 2017 Jul 1;102(7):2401-2406. doi: 10.1210/jc.2016-1095.
• [4] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
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• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] 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.
• [11] Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): possible mechanisms to explain ATO resistance in vivo. Br J Haematol. 2005 Mar;128(5):636-44.
• [12] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [13] Frequent inactivation of RAMP2, EFEMP1 and Dutt1 in lung cancer by promoter hypermethylation. Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4336-44. doi: 10.1158/1078-0432.CCR-07-0015.
• [14] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [15] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [16] 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.
• [17] 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.
• [18] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] 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.
• [21] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [22] 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.
• [23] 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.
• [24] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [25] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.