Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3VVVUO)

• DOT Name: Semaphorin-6B (SEMA6B)
• Synonyms: Semaphorin-Z; Sema Z
• Gene Name: SEMA6B
• Related Disease:
  Rheumatoid arthritis
  Adult glioblastoma
  Breast adenocarcinoma
  Epilepsy, progressive myoclonic, 11
  Glioblastoma multiforme
  Neoplasm
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Nervous system inflammation
• UniProt ID: SEM6B_HUMAN
• Pfam ID: PF01437 ; PF01403
• Sequence:
  MQTPRASPPRPALLLLLLLLGGAHGLFPEEPPPLSVAPRDYLNHYPVFVGSGPGRLTPAE
  GADDLNIQRVLRVNRTLFIGDRDNLYRVELEPPTSTELRYQRKLTWRSNPSDINVCRMKG
  KQEGECRNFVKVLLLRDESTLFVCGSNAFNPVCANYSIDTLQPVGDNISGMARCPYDPKH
  ANVALFSDGMLFTATVTDFLAIDAVIYRSLGDRPTLRTVKHDSKWFKEPYFVHAVEWGSH
  VYFFFREIAMEFNYLEKVVVSRVARVCKNDVGGSPRVLEKQWTSFLKARLNCSVPGDSHF
  YFNVLQAVTGVVSLGGRPVVLAVFSTPSNSIPGSAVCAFDLTQVAAVFEGRFREQKSPES
  IWTPVPEDQVPRPRPGCCAAPGMQYNASSALPDDILNFVKTHPLMDEAVPSLGHAPWILR
  TLMRHQLTRVAVDVGAGPWGNQTVVFLGSEAGTVLKFLVRPNASTSGTSGLSVFLEEFET
  YRPDRCGRPGGGETGQRLLSLELDAASGGLLAAFPRCVVRVPVARCQQYSGCMKNCIGSQ
  DPYCGWAPDGSCIFLSPGTRAAFEQDVSGASTSGLGDCTGLLRASLSEDRAGLVSVNLLV
  TSSVAAFVVGAVVSGFSVGWFVGLRERRELARRKDKEAILAHGAGEAVLSVSRLGERRAQ
  GPGGRGGGGGGGAGVPPEALLAPLMQNGWAKATLLQGGPHDLDSGLLPTPEQTPLPQKRL
  PTPHPHPHALGPRAWDHGHPLLPASASSSLLLLAPARAPEQPPAPGEPTPDGRLYAARPG
  RASHGDFPLTPHASPDRRRVVSAPTGPLDPASAADGLPRPWSPPPTGSLRRPLGPHAPPA
  ATLRRTHTFNSGEARPGDRHRGCHARPGTDLAHLLPYGGADRTAPPVP
• Function: Functions as a cell surface repellent for mossy fibers of developing neurons in the hippocampus where it plays a role in axon guidance. May function through the PLXNA4 receptor expressed by mossy cell axons; (Microbial infection) Acts as a receptor for P.sordellii toxin TcsL in the in the vascular endothelium.
• Tissue Specificity: Expressed in the brain in GABAergic neurons.
• 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
Rheumatoid arthritis	DISTSB4J	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[2]
Breast adenocarcinoma	DISMPHJ0	Strong	Altered Expression	[3]
Epilepsy, progressive myoclonic, 11	DISM3CDB	Strong	Autosomal dominant	[4]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[6]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[6]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[6]
Nervous system inflammation	DISB3X5A	Limited	Altered Expression	[7]

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 Semaphorin-6B (SEMA6B).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Semaphorin-6B (SEMA6B).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Semaphorin-6B (SEMA6B).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Semaphorin-6B (SEMA6B).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Semaphorin-6B (SEMA6B).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Semaphorin-6B (SEMA6B).	[11]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Semaphorin-6B (SEMA6B).	[12]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Semaphorin-6B (SEMA6B).	[3]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Semaphorin-6B (SEMA6B).	[3]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Semaphorin-6B (SEMA6B).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Semaphorin-6B (SEMA6B).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Semaphorin-6B (SEMA6B).	[17]

References

• [1] RNA sequencing to predict response to TNF- inhibitors reveals possible mechanism for nonresponse in smokers.Expert Rev Clin Immunol. 2018 Jul;14(7):623-633. doi: 10.1080/1744666X.2018.1480937. Epub 2018 Jun 6.
• [2] Human semaphorin 6B [(HSA)SEMA6B], a novel human class 6 semaphorin gene: alternative splicing and all-trans-retinoic acid-dependent downregulation in glioblastoma cell lines.Genomics. 2001 May 1;73(3):343-8. doi: 10.1006/geno.2001.6525.
• [3] Effects of PPAR and RXR ligands in semaphorin 6B gene expression of human MCF-7 breast cancer cells. Int J Oncol. 2006 Apr;28(4):977-84.
• [4] De Novo Truncating Variants in the Last Exon of SEMA6B Cause Progressive Myoclonic Epilepsy. Am J Hum Genet. 2020 Apr 2;106(4):549-558. doi: 10.1016/j.ajhg.2020.02.011. Epub 2020 Mar 12.
• [5] Plexin-A4 promotes tumor progression and tumor angiogenesis by enhancement of VEGF and bFGF signaling.Blood. 2011 Oct 13;118(15):4285-96. doi: 10.1182/blood-2011-03-341388. Epub 2011 Aug 10.
• [6] Analysis of SEMA6B gene expression in breast cancer: identification of a new isoform.Biochim Biophys Acta. 2013 Oct;1830(10):4543-53. doi: 10.1016/j.bbagen.2013.05.003. Epub 2013 May 9.
• [7] An interferon--resistant and NLRP3 inflammasome-independent subtype of EAE with neuronal damage.Nat Neurosci. 2016 Dec;19(12):1599-1609. doi: 10.1038/nn.4421. Epub 2016 Nov 7.
• [8] 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.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [13] Effects of PPAR and RXR ligands in semaphorin 6B gene expression of human MCF-7 breast cancer cells. Int J Oncol. 2006 Apr;28(4):977-84.
• [14] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.