Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD5TJV1)

• DOT Name: Semaphorin-3D (SEMA3D)
• Gene Name: SEMA3D
• Related Disease:
  Adult glioblastoma
  Colorectal carcinoma
  Glioblastoma multiforme
  Hyperparathyroidism
  Neoplasm
  Osteoarthritis
  Schizophrenia
  Hirschsprung disease
  Meniere disease
  Metastatic malignant neoplasm
  Pancreatic cancer
  Patent ductus arteriosus
• UniProt ID: SEM3D_HUMAN
• Pfam ID: PF18452 ; PF01403
• Sequence:
  MNANKDERLKARSQDFHLFPALMMLSMTMLFLPVTGTLKQNIPRLKLTYKDLLLSNSCIP
  FLGSSEGLDFQTLLLDEERGRLLLGAKDHIFLLSLVDLNKNFKKIYWPAAKERVELCKLA
  GKDANTECANFIRVLQPYNKTHIYVCGTGAFHPICGYIDLGVYKEDIIFKLDTHNLESGR
  LKCPFDPQQPFASVMTDEYLYSGTASDFLGKDTAFTRSLGPTHDHHYIRTDISEHYWLNG
  AKFIGTFFIPDTYNPDDDKIYFFFRESSQEGSTSDKTILSRVGRVCKNDVGGQRSLINKW
  TTFLKARLICSIPGSDGADTYFDELQDIYLLPTRDERNPVVYGVFTTTSSIFKGSAVCVY
  SMADIRAVFNGPYAHKESADHRWVQYDGRIPYPRPGTCPSKTYDPLIKSTRDFPDDVISF
  IKRHSVMYKSVYPVAGGPTFKRINVDYRLTQIVVDHVIAEDGQYDVMFLGTDIGTVLKVV
  SISKEKWNMEEVVLEELQIFKHSSIILNMELSLKQQQLYIGSRDGLVQLSLHRCDTYGKA
  CADCCLARDPYCAWDGNACSRYAPTSKRRARRQDVKYGDPITQCWDIEDSISHETADEKV
  IFGIEFNSTFLECIPKSQQATIKWYIQRSGDEHREELKPDERIIKTEYGLLIRSLQKKDS
  GMYYCKAQEHTFIHTIVKLTLNVIENEQMENTQRAEHEEGKVKDLLAESRLRYKDYIQIL
  SSPNFSLDQYCEQMWHREKRRQRNKGGPKWKHMQEMKKKRNRRHHRDLDELPRAVAT
• Function: Induces the collapse and paralysis of neuronal growth cones. Could potentially act as repulsive cues toward specific neuronal populations. Binds to neuropilin.
• KEGG Pathway: Axon guidance (hsa04360)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[2]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Hyperparathyroidism	DIS4FVAT	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[5]
Schizophrenia	DISSRV2N	Strong	Biomarker	[6]
Hirschsprung disease	DISUUSM1	moderate	Genetic Variation	[7]
Meniere disease	DISC5R5F	Limited	Genetic Variation	[8]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[4]
Pancreatic cancer	DISJC981	Limited	Biomarker	[9]
Patent ductus arteriosus	DIS9P8YS	Limited	Biomarker	[9]

10 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 Semaphorin-3D (SEMA3D).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Semaphorin-3D (SEMA3D).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Semaphorin-3D (SEMA3D).	[12]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Semaphorin-3D (SEMA3D).	[13]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Semaphorin-3D (SEMA3D).	[14]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Semaphorin-3D (SEMA3D).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Semaphorin-3D (SEMA3D).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Semaphorin-3D (SEMA3D).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Semaphorin-3D (SEMA3D).	[18]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Semaphorin-3D (SEMA3D).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Semaphorin-3D (SEMA3D).	[20]

References

• [1] Semaphorin-3D and semaphorin-3E inhibit the development of tumors from glioblastoma cells implanted in the cortex of the brain.PLoS One. 2012;7(8):e42912. doi: 10.1371/journal.pone.0042912. Epub 2012 Aug 24.
• [2] Decreased expression of semaphorin 3D is associated with genesis and development in colorectal cancer.World J Surg Oncol. 2017 Mar 20;15(1):67. doi: 10.1186/s12957-017-1128-1.
• [3] Deficiency in the secreted protein Semaphorin3d causes abnormal parathyroid development in mice.J Biol Chem. 2019 May 24;294(21):8336-8347. doi: 10.1074/jbc.RA118.007063. Epub 2019 Apr 12.
• [4] Axon Guidance Molecules Promote Perineural Invasion and Metastasis of Orthotopic Pancreatic Tumors in Mice.Gastroenterology. 2019 Sep;157(3):838-850.e6. doi: 10.1053/j.gastro.2019.05.065. Epub 2019 Jun 1.
• [5] Leptin changes differentiation fate and induces senescence in chondrogenic progenitor cells.Cell Death Dis. 2016 Apr 14;7(4):e2188. doi: 10.1038/cddis.2016.68.
• [6] Possible association of the semaphorin 3D gene (SEMA3D) with schizophrenia.J Psychiatr Res. 2011 Jan;45(1):47-53. doi: 10.1016/j.jpsychires.2010.05.004. Epub 2010 Jun 1.
• [7] Testing the Ret and Sema3d genetic interaction in mouse enteric nervous system development.Hum Mol Genet. 2017 May 15;26(10):1811-1820. doi: 10.1093/hmg/ddx084.
• [8] Variable expressivity and genetic heterogeneity involving DPT and SEMA3D genes in autosomal dominant familial Meniere's disease.Eur J Hum Genet. 2017 Feb;25(2):200-207. doi: 10.1038/ejhg.2016.154. Epub 2016 Nov 23.
• [9] Semaphorin 3D autocrine signaling mediates the metastatic role of annexin A2 in pancreatic cancer.Sci Signal. 2015 Aug 4;8(388):ra77. doi: 10.1126/scisignal.aaa5823.
• [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] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [12] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] 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.
• [15] 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.
• [16] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [17] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [18] 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.
• [19] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [20] 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.