Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1Y3YZD)

• DOT Name: Semaphorin-4B (SEMA4B)
• Synonyms: Semaphorin-C
• Gene Name: SEMA4B
• Related Disease:
  Glioma
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Prostate cancer
  Prostate carcinoma
  Tendinopathy
  Intellectual disability
  Schizophrenia
  Non-small-cell lung cancer
• UniProt ID: SEM4B_HUMAN
• Pfam ID: PF01437 ; PF01403
• Sequence:
  MLRTAMGLRSWLAAPWGALPPRPPLLLLLLLLLLLQPPPPTWALSPRISLPLGSEERPFL
  RFEAEHISNYTALLLSRDGRTLYVGAREALFALSSNLSFLPGGEYQELLWGADAEKKQQC
  SFKGKDPQRDCQNYIKILLPLSGSHLFTCGTAAFSPMCTYINMENFTLARDEKGNVLLED
  GKGRCPFDPNFKSTALVVDGELYTGTVSSFQGNDPAISRSQSLRPTKTESSLNWLQDPAF
  VASAYIPESLGSLQGDDDKIYFFFSETGQEFEFFENTIVSRIARICKGDEGGERVLQQRW
  TSFLKAQLLCSRPDDGFPFNVLQDVFTLSPSPQDWRDTLFYGVFTSQWHRGTTEGSAVCV
  FTMKDVQRVFSGLYKEVNRETQQWYTVTHPVPTPRPGACITNSARERKINSSLQLPDRVL
  NFLKDHFLMDGQVRSRMLLLQPQARYQRVAVHRVPGLHHTYDVLFLGTGDGRLHKAVSVG
  PRVHIIEELQIFSSGQPVQNLLLDTHRGLLYAASHSGVVQVPMANCSLYRSCGDCLLARD
  PYCAWSGSSCKHVSLYQPQLATRPWIQDIEGASAKDLCSASSVVSPSFVPTGEKPCEQVQ
  FQPNTVNTLACPLLSNLATRLWLRNGAPVNASASCHVLPTGDLLLVGTQQLGEFQCWSLE
  EGFQQLVASYCPEVVEDGVADQTDEGGSVPVIISTSRVSAPAGGKASWGADRSYWKEFLV
  MCTLFVLAVLLPVLFLLYRHRNSMKVFLKQGECASVHPKTCPVVLPPETRPLNGLGPPST
  PLDHRGYQSLSDSPPGSRVFTESEKRPLSIQDSFVEVSPVCPRPRVRLGSEIRDSVV
• Function: Inhibits axonal extension by providing local signals to specify territories inaccessible for growing axons.
• KEGG Pathway: Axon guidance (hsa04360)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioma	DIS5RPEH	Strong	Biomarker	[1]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung carcinoma	DISTR26C	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	Strong	Altered Expression	[4]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[4]
Tendinopathy	DISJH7UX	Strong	Biomarker	[5]
Intellectual disability	DISMBNXP	Disputed	Genetic Variation	[6]
Schizophrenia	DISSRV2N	Disputed	Genetic Variation	[6]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Semaphorin-4B (SEMA4B).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Semaphorin-4B (SEMA4B).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Semaphorin-4B (SEMA4B).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Semaphorin-4B (SEMA4B).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Semaphorin-4B (SEMA4B).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Semaphorin-4B (SEMA4B).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Semaphorin-4B (SEMA4B).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Semaphorin-4B (SEMA4B).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Semaphorin-4B (SEMA4B).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Semaphorin-4B (SEMA4B).	[20]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Semaphorin-4B (SEMA4B).	[21]

3 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 Semaphorin-4B (SEMA4B).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Semaphorin-4B (SEMA4B).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Semaphorin-4B (SEMA4B).	[19]

References

• [1] Combined shRNA over CRISPR/cas9 as a methodology to detect off-target effects and a potential compensatory mechanism.Sci Rep. 2018 Jan 8;8(1):93. doi: 10.1038/s41598-017-18551-z.
• [2] Label-free quantitative proteomics and N-glycoproteomics analysis of KRAS-activated human bronchial epithelial cells.Mol Cell Proteomics. 2012 Oct;11(10):901-15. doi: 10.1074/mcp.M112.020875. Epub 2012 Jul 3.
• [3] Hypoxia and hypoxia-inducible factor 1 repress SEMA4B expression to promote non-small cell lung cancer invasion.Tumour Biol. 2014 May;35(5):4949-55. doi: 10.1007/s13277-014-1651-4. Epub 2014 Jan 29.
• [4] Prostate cancer tissues with positive TMPRSS2-ERG-gene-fusion status may display enhanced nerve density.Urol Oncol. 2020 Jan;38(1):3.e7-3.e15. doi: 10.1016/j.urolonc.2018.07.019. Epub 2018 Sep 18.
• [5] Metal artifact reduction MRI of total ankle arthroplasty implants.Eur Radiol. 2018 May;28(5):2216-2227. doi: 10.1007/s00330-017-5153-9. Epub 2017 Dec 7.
• [6] Differential DNA methylation at birth associated with mental disorder in individuals with 22q11.2 deletion syndrome.Transl Psychiatry. 2017 Aug 29;7(8):e1221. doi: 10.1038/tp.2017.181.
• [7] SEMA4B inhibits growth of non-small cell lung cancer in vitro and in vivo.Cell Signal. 2015 Jun;27(6):1208-13. doi: 10.1016/j.cellsig.2015.02.027. Epub 2015 Mar 4.
• [8] 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.
• [9] 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.
• [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] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [13] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [14] 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.
• [15] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [16] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [19] 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.
• [20] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [21] 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.