Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT35RBNT)

• DOT Name: Slit homolog 1 protein (SLIT1)
• Synonyms: Slit-1; Multiple epidermal growth factor-like domains protein 4; Multiple EGF-like domains protein 4
• Gene Name: SLIT1
• Related Disease:
  Breast neoplasm
  Colorectal carcinoma
  Colorectal neoplasm
  Glioma
  Neoplasm
  Bipolar disorder
• UniProt ID: SLIT1_HUMAN
• Pfam ID: PF00008 ; PF12661 ; PF02210 ; PF13855 ; PF01463 ; PF01462
• Sequence:
  MALTPGWGSSAGPVRPELWLLLWAAAWRLGASACPALCTCTGTTVDCHGTGLQAIPKNIP
  RNTERLELNGNNITRIHKNDFAGLKQLRVLQLMENQIGAVERGAFDDMKELERLRLNRNQ
  LHMLPELLFQNNQALSRLDLSENAIQAIPRKAFRGATDLKNLQLDKNQISCIEEGAFRAL
  RGLEVLTLNNNNITTIPVSSFNHMPKLRTFRLHSNHLFCDCHLAWLSQWLRQRPTIGLFT
  QCSGPASLRGLNVAEVQKSEFSCSGQGEAGRVPTCTLSSGSCPAMCTCSNGIVDCRGKGL
  TAIPANLPETMTEIRLELNGIKSIPPGAFSPYRKLRRIDLSNNQIAEIAPDAFQGLRSLN
  SLVLYGNKITDLPRGVFGGLYTLQLLLLNANKINCIRPDAFQDLQNLSLLSLYDNKIQSL
  AKGTFTSLRAIQTLHLAQNPFICDCNLKWLADFLRTNPIETSGARCASPRRLANKRIGQI
  KSKKFRCSAKEQYFIPGTEDYQLNSECNSDVVCPHKCRCEANVVECSSLKLTKIPERIPQ
  STAELRLNNNEISILEATGMFKKLTHLKKINLSNNKVSEIEDGAFEGAASVSELHLTANQ
  LESIRSGMFRGLDGLRTLMLRNNRISCIHNDSFTGLRNVRLLSLYDNQITTVSPGAFDTL
  QSLSTLNLLANPFNCNCQLAWLGGWLRKRKIVTGNPRCQNPDFLRQIPLQDVAFPDFRCE
  EGQEEGGCLPRPQCPQECACLDTVVRCSNKHLRALPKGIPKNVTELYLDGNQFTLVPGQL
  STFKYLQLVDLSNNKISSLSNSSFTNMSQLTTLILSYNALQCIPPLAFQGLRSLRLLSLH
  GNDISTLQEGIFADVTSLSHLAIGANPLYCDCHLRWLSSWVKTGYKEPGIARCAGPQDME
  GKLLLTTPAKKFECQGPPTLAVQAKCDLCLSSPCQNQGTCHNDPLEVYRCACPSGYKGRD
  CEVSLDSCSSGPCENGGTCHAQEGEDAPFTCSCPTGFEGPTCGVNTDDCVDHACANGGVC
  VDGVGNYTCQCPLQYEGKACEQLVDLCSPDLNPCQHEAQCVGTPDGPRCECMPGYAGDNC
  SENQDDCRDHRCQNGAQCMDEVNSYSCLCAEGYSGQLCEIPPHLPAPKSPCEGTECQNGA
  NCVDQGNRPVCQCLPGFGGPECEKLLSVNFVDRDTYLQFTDLQNWPRANITLQVSTAEDN
  GILLYNGDNDHIAVELYQGHVRVSYDPGSYPSSAIYSAETINDGQFHTVELVAFDQMVNL
  SIDGGSPMTMDNFGKHYTLNSEAPLYVGGMPVDVNSAAFRLWQILNGTGFHGCIRNLYIN
  NELQDFTKTQMKPGVVPGCEPCRKLYCLHGICQPNATPGPMCHCEAGWVGLHCDQPADGP
  CHGHKCVHGQCVPLDALSYSCQCQDGYSGALCNQAGALAEPCRGLQCLHGHCQASGTKGA
  HCVCDPGFSGELCEQESECRGDPVRDFHQVQRGYAICQTTRPLSWVECRGSCPGQGCCQG
  LRLKRRKFTFECSDGTSFAEEVEKPTKCGCALCA
• Function: Thought to act as molecular guidance cue in cellular migration, and function appears to be mediated by interaction with roundabout homolog receptors. During neural development involved in axonal navigation at the ventral midline of the neural tube and projection of axons to different regions. SLIT1 and SLIT2 together seem to be essential for midline guidance in the forebrain by acting as repulsive signal preventing inappropriate midline crossing by axons projecting from the olfactory bulb.
• Tissue Specificity: Predominantly expressed in adult forebrain. Expressed in fetal brain, lung and kidney.
• KEGG Pathway: Axon guidance (hsa04360)
• Reactome Pathway:
  Signaling by ROBO receptors (R-HSA-376176)
  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)
  Netrin-1 signaling (R-HSA-373752)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast neoplasm	DISNGJLM	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Posttranslational Modification	[4]
Neoplasm	DISZKGEW	Strong	Posttranslational Modification	[4]
Bipolar disorder	DISAM7J2	moderate	Genetic Variation	[5]

3 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 Slit homolog 1 protein (SLIT1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Slit homolog 1 protein (SLIT1).	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Slit homolog 1 protein (SLIT1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Slit homolog 1 protein (SLIT1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Slit homolog 1 protein (SLIT1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Slit homolog 1 protein (SLIT1).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Slit homolog 1 protein (SLIT1).	[10]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Slit homolog 1 protein (SLIT1).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Slit homolog 1 protein (SLIT1).	[10]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Slit homolog 1 protein (SLIT1).	[8]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of Slit homolog 1 protein (SLIT1).	[8]
Gentamicin	DMKINJO	Approved	Gentamicin decreases the expression of Slit homolog 1 protein (SLIT1).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Slit homolog 1 protein (SLIT1).	[10]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Slit homolog 1 protein (SLIT1).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Slit homolog 1 protein (SLIT1).	[13]

References

• [1] SLITs suppress tumor growth in vivo by silencing Sdf1/Cxcr4 within breast epithelium.Cancer Res. 2008 Oct 1;68(19):7819-27. doi: 10.1158/0008-5472.CAN-08-1357.
• [2] SUV39H2 promotes colorectal cancer proliferation and metastasis via tri-methylation of the SLIT1 promoter.Cancer Lett. 2018 May 28;422:56-69. doi: 10.1016/j.canlet.2018.02.023. Epub 2018 Feb 16.
• [3] HOXB13, a target of DNMT3B, is methylated at an upstream CpG island, and functions as a tumor suppressor in primary colorectal tumors.PLoS One. 2010 Apr 29;5(4):e10338. doi: 10.1371/journal.pone.0010338.
• [4] Epigenetic inactivation of SLIT3 and SLIT1 genes in human cancers.Br J Cancer. 2004 Dec 13;91(12):2071-8. doi: 10.1038/sj.bjc.6602222.
• [5] A genome-wide association study identifies two novel susceptibility loci and trans population polygenicity associated with bipolar disorder.Mol Psychiatry. 2018 Mar;23(3):639-647. doi: 10.1038/mp.2016.259. Epub 2017 Jan 24.
• [6] 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.
• [7] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [8] Effect of nephrotoxicants and hepatotoxicants on gene expression profile in human peripheral blood mononuclear cells. Biochem Biophys Res Commun. 2010 Oct 15;401(2):245-50. doi: 10.1016/j.bbrc.2010.09.039. Epub 2010 Sep 16.
• [9] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [10] 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.
• [11] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [12] 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.
• [13] 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.
• [14] 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.