Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLS2RJ4)

• DOT Name: Slit homolog 2 protein (SLIT2)
• Synonyms: Slit-2
• Gene Name: SLIT2
• UniProt ID: SLIT2_HUMAN
• PDB ID: 2V70; 2V9S; 2V9T; 2WFH
• Pfam ID: PF00008 ; PF12661 ; PF00054 ; PF00560 ; PF13855 ; PF01463 ; PF01462
• Sequence:
  MRGVGWQMLSLSLGLVLAILNKVAPQACPAQCSCSGSTVDCHGLALRSVPRNIPRNTERL
  DLNGNNITRITKTDFAGLRHLRVLQLMENKISTIERGAFQDLKELERLRLNRNHLQLFPE
  LLFLGTAKLYRLDLSENQIQAIPRKAFRGAVDIKNLQLDYNQISCIEDGAFRALRDLEVL
  TLNNNNITRLSVASFNHMPKLRTFRLHSNNLYCDCHLAWLSDWLRQRPRVGLYTQCMGPS
  HLRGHNVAEVQKREFVCSGHQSFMAPSCSVLHCPAACTCSNNIVDCRGKGLTEIPTNLPE
  TITEIRLEQNTIKVIPPGAFSPYKKLRRIDLSNNQISELAPDAFQGLRSLNSLVLYGNKI
  TELPKSLFEGLFSLQLLLLNANKINCLRVDAFQDLHNLNLLSLYDNKLQTIAKGTFSPLR
  AIQTMHLAQNPFICDCHLKWLADYLHTNPIETSGARCTSPRRLANKRIGQIKSKKFRCSA
  KEQYFIPGTEDYRSKLSGDCFADLACPEKCRCEGTTVDCSNQKLNKIPEHIPQYTAELRL
  NNNEFTVLEATGIFKKLPQLRKINFSNNKITDIEEGAFEGASGVNEILLTSNRLENVQHK
  MFKGLESLKTLMLRSNRITCVGNDSFIGLSSVRLLSLYDNQITTVAPGAFDTLHSLSTLN
  LLANPFNCNCYLAWLGEWLRKKRIVTGNPRCQKPYFLKEIPIQDVAIQDFTCDDGNDDNS
  CSPLSRCPTECTCLDTVVRCSNKGLKVLPKGIPRDVTELYLDGNQFTLVPKELSNYKHLT
  LIDLSNNRISTLSNQSFSNMTQLLTLILSYNRLRCIPPRTFDGLKSLRLLSLHGNDISVV
  PEGAFNDLSALSHLAIGANPLYCDCNMQWLSDWVKSEYKEPGIARCAGPGEMADKLLLTT
  PSKKFTCQGPVDVNILAKCNPCLSNPCKNDGTCNSDPVDFYRCTCPYGFKGQDCDVPIHA
  CISNPCKHGGTCHLKEGEEDGFWCICADGFEGENCEVNVDDCEDNDCENNSTCVDGINNY
  TCLCPPEYTGELCEEKLDFCAQDLNPCQHDSKCILTPKGFKCDCTPGYVGEHCDIDFDDC
  QDNKCKNGAHCTDAVNGYTCICPEGYSGLFCEFSPPMVLPRTSPCDNFDCQNGAQCIVRI
  NEPICQCLPGYQGEKCEKLVSVNFINKESYLQIPSAKVRPQTNITLQIATDEDSGILLYK
  GDKDHIAVELYRGRVRASYDTGSHPASAIYSVETINDGNFHIVELLALDQSLSLSVDGGN
  PKIITNLSKQSTLNFDSPLYVGGMPGKSNVASLRQAPGQNGTSFHGCIRNLYINSELQDF
  QKVPMQTGILPGCEPCHKKVCAHGTCQPSSQAGFTCECQEGWMGPLCDQRTNDPCLGNKC
  VHGTCLPINAFSYSCKCLEGHGGVLCDEEEDLFNPCQAIKCKHGKCRLSGLGQPYCECSS
  GYTGDSCDREISCRGERIRDYYQKQQGYAACQTTKKVSRLECRGGCAGGQCCGPLRSKRR
  KYSFECTDGSSFVDEVEKVVKCGCTRCVS
• 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 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. In spinal cord development may play a role in guiding commissural axons once they reached the floor plate by modulating the response to netrin. In vitro, silences the attractive effect of NTN1 but not its growth-stimulatory effect and silencing requires the formation of a ROBO1-DCC complex. May be implicated in spinal cord midline post-crossing axon repulsion. In vitro, only commissural axons that crossed the midline responded to SLIT2. In the developing visual system appears to function as repellent for retinal ganglion axons by providing a repulsion that directs these axons along their appropriate paths prior to, and after passage through, the optic chiasm. In vitro, collapses and repels retinal ganglion cell growth cones. Seems to play a role in branching and arborization of CNS sensory axons, and in neuronal cell migration. In vitro, Slit homolog 2 protein N-product, but not Slit homolog 2 protein C-product, repels olfactory bulb (OB) but not dorsal root ganglia (DRG) axons, induces OB growth cones collapse and induces branching of DRG axons. Seems to be involved in regulating leukocyte migration.
• Tissue Specificity: Fetal lung and kidney, and adult spinal cord. Weak expression in adult adrenal gland, thyroid, trachea and other tissues examined.
• 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 expression of SLITs and ROBOs (R-HSA-9010553)
  Netrin-1 signaling (R-HSA-373752)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
NAPQI	DM8F5LR	Investigative	Slit homolog 2 protein (SLIT2) affects the response to substance of NAPQI.	[27]

27 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 Slit homolog 2 protein (SLIT2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Slit homolog 2 protein (SLIT2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Slit homolog 2 protein (SLIT2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Slit homolog 2 protein (SLIT2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Slit homolog 2 protein (SLIT2).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Slit homolog 2 protein (SLIT2).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Slit homolog 2 protein (SLIT2).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Slit homolog 2 protein (SLIT2).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Slit homolog 2 protein (SLIT2).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Slit homolog 2 protein (SLIT2).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Slit homolog 2 protein (SLIT2).	[11]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Slit homolog 2 protein (SLIT2).	[12]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Slit homolog 2 protein (SLIT2).	[8]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Slit homolog 2 protein (SLIT2).	[14]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Slit homolog 2 protein (SLIT2).	[15]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Slit homolog 2 protein (SLIT2).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Slit homolog 2 protein (SLIT2).	[17]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Slit homolog 2 protein (SLIT2).	[8]
PD-0325901	DM27D4J	Phase 2	PD-0325901 decreases the expression of Slit homolog 2 protein (SLIT2).	[18]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 increases the expression of Slit homolog 2 protein (SLIT2).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Slit homolog 2 protein (SLIT2).	[21]
Mivebresib	DMCPF90	Phase 1	Mivebresib increases the expression of Slit homolog 2 protein (SLIT2).	[19]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Slit homolog 2 protein (SLIT2).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Slit homolog 2 protein (SLIT2).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Slit homolog 2 protein (SLIT2).	[24]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Slit homolog 2 protein (SLIT2).	[25]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone increases the expression of Slit homolog 2 protein (SLIT2).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Slit homolog 2 protein (SLIT2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Slit homolog 2 protein (SLIT2).	[20]

References

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• [11] Epigenetic inactivation of SLIT2 in human hepatocellular carcinomas. Biochem Biophys Res Commun. 2009 Jan 30;379(1):86-91. doi: 10.1016/j.bbrc.2008.12.022. Epub 2008 Dec 17.
• [12] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [13] 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.
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• [15] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [16] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
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• [18] PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.
• [19] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [20] 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.
• [21] 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.
• [22] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [23] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [24] 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.
• [25] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [26] 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.
• [27] Acetaminophen-NAPQI hepatotoxicity: a cell line model system genome-wide association study. Toxicol Sci. 2011 Mar;120(1):33-41. doi: 10.1093/toxsci/kfq375. Epub 2010 Dec 22.