Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCA7JIT)

• DOT Name: Plexin-B1 (PLXNB1)
• Synonyms: Semaphorin receptor SEP
• Gene Name: PLXNB1
• Related Disease:
  Becker muscular dystrophy
  Cervical cancer
  Cervical carcinoma
  Duchenne muscular dystrophy
  Neurodevelopmental disorder
  Subarachnoid hemorrhage
  Advanced cancer
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Castration-resistant prostate carcinoma
  Cerebral palsy
  Depression
  Esophageal cancer
  Hepatitis C virus infection
  Metastatic malignant neoplasm
  Neoplasm
  Osteoarthritis
  Schizophrenia
  Small lymphocytic lymphoma
  Stroke
  Bone disease
  Head-neck squamous cell carcinoma
  Juvenile myoclonic epilepsy
  Laryngeal squamous cell carcinoma
  Plasma cell myeloma
  Prostate cancer
  Prostate carcinoma
  Adenocarcinoma
  AIDS-related lymphoma
  Epithelial ovarian cancer
  Generalized pustular psoriasis
  Melanoma
  Ovarian cancer
  Ovarian neoplasm
• UniProt ID: PLXB1_HUMAN
• PDB ID: 2JPH; 2OS6; 2R2O; 2REX; 3HM6; 3OL2; 3SU8; 3SUA; 5B4W; 7VF3; 7VG7; 8B3K
• Pfam ID: PF08337 ; PF20170 ; PF01437 ; PF01403 ; PF01833 ; PF18020 ; PF17960
• Sequence:
  MPALGPALLQALWAGWVLTLQPLPPTAFTPNGTYLQHLARDPTSGTLYLGATNFLFQLSP
  GLQLEATVSTGPVLDSRDCLPPVMPDECPQAQPTNNPNQLLLVSPGALVVCGSVHQGVCE
  QRRLGQLEQLLLRPERPGDTQYVAANDPAVSTVGLVAQGLAGEPLLFVGRGYTSRGVGGG
  IPPITTRALWPPDPQAAFSYEETAKLAVGRLSEYSHHFVSAFARGASAYFLFLRRDLQAQ
  SRAFRAYVSRVCLRDQHYYSYVELPLACEGGRYGLIQAAAVATSREVAHGEVLFAAFSSA
  APPTVGRPPSAAAGASGASALCAFPLDEVDRLANRTRDACYTREGRAEDGTEVAYIEYDV
  NSDCAQLPVDTLDAYPCGSDHTPSPMASRVPLEATPILEWPGIQLTAVAVTMEDGHTIAF
  LGDSQGQLHRVYLGPGSDGHPYSTQSIQQGSAVSRDLTFDGTFEHLYVMTQSTLLKVPVA
  SCAQHLDCASCLAHRDPYCGWCVLLGRCSRRSECSRGQGPEQWLWSFQPELGCLQVAAMS
  PANISREETREVFLSVPDLPPLWPGESYSCHFGEHQSPALLTGSGVMCPSPDPSEAPVLP
  RGADYVSVSVELRFGAVVIAKTSLSFYDCVAVTELRPSAQCQACVSSRWGCNWCVWQHLC
  THKASCDAGPMVASHQSPLVSPDPPARGGPSPSPPTAPKALATPAPDTLPVEPGAPSTAT
  ASDISPGASPSLLSPWGPWAGSGSISSPGSTGSPLHEEPSPPSPQNGPGTAVPAPTDFRP
  SATPEDLLASPLSPSEVAAVPPADPGPEALHPTVPLDLPPATVPATTFPGAMGSVKPALD
  WLTREGGELPEADEWTGGDAPAFSTSTLLSGDGDSAELEGPPAPLILPSSLDYQYDTPGL
  WELEEATLGASSCPCVESVQGSTLMPVHVEREIRLLGRNLHLFQDGPGDNECVMELEGLE
  VVVEARVECEPPPDTQCHVTCQQHQLSYEALQPELRVGLFLRRAGRLRVDSAEGLHVVLY
  DCSVGHGDCSRCQTAMPQYGCVWCEGERPRCVTREACGEAEAVATQCPAPLIHSVEPLTG
  PVDGGTRVTIRGSNLGQHVQDVLGMVTVAGVPCAVDAQEYEVSSSLVCITGASGEEVAGA
  TAVEVPGRGRGVSEHDFAYQDPKVHSIFPARGPRAGGTRLTLNGSKLLTGRLEDIRVVVG
  DQPCHLLPEQQSEQLRCETSPRPTPATLPVAVWFGATERRLQRGQFKYTLDPNITSAGPT
  KSFLSGGREICVRGQNLDVVQTPRIRVTVVSRMLQPSQGLGRRRRVVPETACSLGPSCSS
  QQFEEPCHVNSSQLITCRTPALPGLPEDPWVRVEFILDNLVFDFATLNPTPFSYEADPTL
  QPLNPEDPTMPFRHKPGSVFSVEGENLDLAMSKEEVVAMIGDGPCVVKTLTRHHLYCEPP
  VEQPLPRHHALREAPDSLPEFTVQMGNLRFSLGHVQYDGESPGAFPVAAQVGLGVGTSLL
  ALGVIIIVLMYRRKSKQALRDYKKVQIQLENLESSVRDRCKKEFTDLMTEMTDLTSDLLG
  SGIPFLDYKVYAERIFFPGHRESPLHRDLGVPESRRPTVEQGLGQLSNLLNSKLFLTKFI
  HTLESQRTFSARDRAYVASLLTVALHGKLEYFTDILRTLLSDLVAQYVAKNPKLMLRRTE
  TVVEKLLTNWMSICLYTFVRDSVGEPLYMLFRGIKHQVDKGPVDSVTGKAKYTLNDNRLL
  REDVEYRPLTLNALLAVGPGAGEAQGVPVKVLDCDTISQAKEKMLDQLYKGVPLTQRPDP
  RTLDVEWRSGVAGHLILSDEDVTSEVQGLWRRLNTLQHYKVPDGATVALVPCLTKHVLRE
  NQDYVPGERTPMLEDVDEGGIRPWHLVKPSDEPEPPRPRRGSLRGGERERAKAIPEIYLT
  RLLSMKGTLQKFVDDLFQVILSTSRPVPLAVKYFFDLLDEQAQQHGISDQDTIHIWKTNS
  LPLRFWINIIKNPQFVFDVQTSDNMDAVLLVIAQTFMDACTLADHKLGRDSPINKLLYAR
  DIPRYKRMVERYYADIRQTVPASDQEMNSVLAELSWNYSGDLGARVALHELYKYINKYYD
  QIITALEEDGTAQKMQLGYRLQQIAAAVENKVTDL
• Function: Receptor for SEMA4D. Plays a role in GABAergic synapse development. Mediates SEMA4A- and SEMA4D-dependent inhibitory synapse development. Plays a role in RHOA activation and subsequent changes of the actin cytoskeleton. Plays a role in axon guidance, invasive growth and cell migration.
• Tissue Specificity: Highly expressed in fetal kidney, and at slightly lower levels in fetal brain, lung and liver.
• KEGG Pathway: Axon guidance (hsa04360)
• Reactome Pathway:
  Sema4D mediated inhibition of cell attachment and migration (R-HSA-416550)
  Sema4D induced cell migration and growth-cone collapse (R-HSA-416572)
  RHOD GTPase cycle (R-HSA-9013405)
  G alpha (12/13) signalling events (R-HSA-416482)

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Becker muscular dystrophy	DIS5IYHL	Definitive	Biomarker	[1]
Cervical cancer	DISFSHPF	Definitive	Altered Expression	[2]
Cervical carcinoma	DIST4S00	Definitive	Altered Expression	[2]
Duchenne muscular dystrophy	DISRQ3NV	Definitive	Biomarker	[1]
Neurodevelopmental disorder	DIS372XH	Definitive	Biomarker	[3]
Subarachnoid hemorrhage	DISI7I8Y	Definitive	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[7]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Biomarker	[8]
Cerebral palsy	DIS82ODL	Strong	Biomarker	[9]
Depression	DIS3XJ69	Strong	Genetic Variation	[10]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[11]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[12]
Metastatic malignant neoplasm	DIS86UK6	Strong	Genetic Variation	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[14]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[15]
Schizophrenia	DISSRV2N	Strong	Biomarker	[16]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[17]
Stroke	DISX6UHX	Strong	Biomarker	[9]
Bone disease	DISE1F82	moderate	Biomarker	[18]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Biomarker	[19]
Juvenile myoclonic epilepsy	DISYXV1N	moderate	Biomarker	[20]
Laryngeal squamous cell carcinoma	DIS9UUVF	moderate	Altered Expression	[21]
Plasma cell myeloma	DIS0DFZ0	moderate	Altered Expression	[18]
Prostate cancer	DISF190Y	moderate	Biomarker	[8]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[8]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[22]
AIDS-related lymphoma	DISSLRAU	Limited	Altered Expression	[23]
Epithelial ovarian cancer	DIS56MH2	Limited	Altered Expression	[24]
Generalized pustular psoriasis	DISTSNLR	Limited	Biomarker	[25]
Melanoma	DIS1RRCY	Limited	Biomarker	[26]
Ovarian cancer	DISZJHAP	Limited	Altered Expression	[24]
Ovarian neoplasm	DISEAFTY	Limited	Altered Expression	[24]

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 Plexin-B1 (PLXNB1).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Plexin-B1 (PLXNB1).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Plexin-B1 (PLXNB1).	[36]

7 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 Plexin-B1 (PLXNB1).	[28]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Plexin-B1 (PLXNB1).	[29]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Plexin-B1 (PLXNB1).	[30]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Plexin-B1 (PLXNB1).	[31]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Plexin-B1 (PLXNB1).	[32]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Plexin-B1 (PLXNB1).	[33]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Plexin-B1 (PLXNB1).	[34]

References

• [1] Extra-muscle involvement in dystrophinopathies: an electroretinography and evoked potential study.J Neurol Sci. 1997 Mar 10;146(2):127-32. doi: 10.1016/s0022-510x(96)00292-4.
• [2] Plexin-B1 is a target of miR-214 in cervical cancer and promotes the growth and invasion of HeLa cells.Int J Biochem Cell Biol. 2011 Apr;43(4):632-41. doi: 10.1016/j.biocel.2011.01.002. Epub 2011 Jan 7.
• [3] Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet. 2017 Apr;49(4):515-526. doi: 10.1038/ng.3792. Epub 2017 Feb 13.
• [4] Amplitude Instability of Somatosensory Evoked Potentials as an Indicator of Delayed Cerebral Ischemia in a Case of Subarachnoid Hemorrhage.Clin EEG Neurosci. 2019 May;50(3):205-209. doi: 10.1177/1550059418804915. Epub 2018 Oct 3.
• [5] Association between prognosis and SEMA4D/Plexin-B1 expression in various malignancies: A meta-analysis.Medicine (Baltimore). 2019 Feb;98(7):e13298. doi: 10.1097/MD.0000000000013298.
• [6] Targeted brain proteomics uncover multiple pathways to Alzheimer's dementia.Ann Neurol. 2018 Jul;84(1):78-88. doi: 10.1002/ana.25266. Epub 2018 Jul 3.
• [7] "Stem cell like" breast cancers-a model for the identification of new prognostic/predictive markers in endocrine responsive breast cancer exemplified by Plexin B1.Eur J Obstet Gynecol Reprod Biol. 2008 Jul;139(1):11-5. doi: 10.1016/j.ejogrb.2008.02.015. Epub 2008 Apr 15.
• [8] SEMA3C drives cancer growth by transactivating multiple receptor tyrosine kinases via Plexin B1.EMBO Mol Med. 2018 Feb;10(2):219-238. doi: 10.15252/emmm.201707689.
• [9] Bedside neurophysiological tests can identify neonates with stroke leading to cerebral palsy.Clin Neurophysiol. 2019 May;130(5):759-766. doi: 10.1016/j.clinph.2019.02.017. Epub 2019 Mar 15.
• [10] The Probability of Neurotransmitter Release Governs AMPA Receptor Trafficking via Activity-Dependent Regulation of mGluR1 Surface Expression.Cell Rep. 2018 Dec 26;25(13):3631-3646.e3. doi: 10.1016/j.celrep.2018.12.010.
• [11] Shared social mechanisms underlying the risk of nine cancers: A life course study.Int J Cancer. 2019 Jan 1;144(1):59-67. doi: 10.1002/ijc.31719. Epub 2018 Oct 26.
• [12] Interferon--Enhanced CD100/Plexin-B1/B2 Interactions Promote Natural Killer Cell Functions in Patients with Chronic Hepatitis C Virus Infection.Front Immunol. 2017 Nov 3;8:1435. doi: 10.3389/fimmu.2017.01435. eCollection 2017.
• [13] ErbB-2 signals through Plexin-B1 to promote breast cancer metastasis.J Clin Invest. 2012 Apr;122(4):1296-305. doi: 10.1172/JCI60568. Epub 2012 Mar 1.
• [14] Combined SEP and anti-PD-L1 antibody produces a synergistic antitumor effect in B16-F10 melanoma-bearing mice.Sci Rep. 2018 Jan 9;8(1):217. doi: 10.1038/s41598-017-18641-y.
• [15] Identification of differentially expressed genes between osteoarthritic and normal trabecular bone from the intertrochanteric region of the proximal femur using cDNA microarray analysis.Bone. 2005 Apr;36(4):635-44. doi: 10.1016/j.bone.2005.02.003.
• [16] SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D(2) Receptor Mechanism of Action.J Pharmacol Exp Ther. 2019 Oct;371(1):1-14. doi: 10.1124/jpet.119.260281. Epub 2019 Aug 1.
• [17] CD100/Plexin-B1 interactions sustain proliferation and survival of normal and leukemic CD5+ B lymphocytes.Blood. 2003 Mar 1;101(5):1962-9. doi: 10.1182/blood-2002-05-1339. Epub 2002 Oct 24.
• [18] Semaphorin 4D correlates with increased bone resorption, hypercalcemia, and disease stage in newly diagnosed patients with multiple myeloma.Blood Cancer J. 2018 May 11;8(5):42. doi: 10.1038/s41408-018-0075-6.
• [19] CD100-plexin-B1 induces epithelial-mesenchymal transition of head and neck squamous cell carcinoma and promotes metastasis.Cancer Lett. 2019 Jul 28;455:1-13. doi: 10.1016/j.canlet.2019.04.013. Epub 2019 Apr 11.
• [20] Somatosensory evoked potentials and EEG findings in siblings of juvenile myoclonic epilepsy patients.Epileptic Disord. 1999 Sep;1(3):173-7.
• [21] Long noncoding RNA ZEB2-AS1 facilitates laryngeal squamous cell carcinoma progression by miR-6840-3p/PLXNB1 axis.Onco Targets Ther. 2019 Sep 6;12:7337-7345. doi: 10.2147/OTT.S212749. eCollection 2019.
• [22] Plexin B1 is downregulated in renal cell carcinomas and modulates cell growth.Transl Res. 2008 Mar;151(3):134-40. doi: 10.1016/j.trsl.2007.12.003. Epub 2008 Jan 7.
• [23] Molecular mechanisms of activating c-MET in KSHV+ primary effusion lymphoma.Oncotarget. 2017 Mar 14;8(11):18373-18380. doi: 10.18632/oncotarget.15444.
• [24] Plexin-B1 silencing inhibits ovarian cancer cell migration and invasion.BMC Cancer. 2010 Nov 8;10:611. doi: 10.1186/1471-2407-10-611.
• [25] Serum Procalcitonin and Presepsin Levels in Patients with Generalized Pustular Psoriasis.Dis Markers. 2018 Dec 16;2018:9758473. doi: 10.1155/2018/9758473. eCollection 2018.
• [26] Sema4D, the ligand for Plexin B1, suppresses c-Met activation and migration and promotes melanocyte survival and growth.J Invest Dermatol. 2012 Apr;132(4):1230-8. doi: 10.1038/jid.2011.414. Epub 2011 Dec 22.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [31] 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.
• [32] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [33] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [34] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [35] 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.
• [36] 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.