Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQJSV7W)

• DOT Name: Semaphorin-3A (SEMA3A)
• Synonyms: Semaphorin III; Sema III
• Gene Name: SEMA3A
• Related Disease:
  Hypogonadotropic hypogonadism 16 with or without anosmia
  Brugada syndrome
  Kallmann syndrome
• UniProt ID: SEM3A_HUMAN
• Pfam ID: PF18452 ; PF01403
• Sequence:
  MGWLTRIVCLFWGVLLTARANYQNGKNNVPRLKLSYKEMLESNNVITFNGLANSSSYHTF
  LLDEERSRLYVGAKDHIFSFDLVNIKDFQKIVWPVSYTRRDECKWAGKDILKECANFIKV
  LKAYNQTHLYACGTGAFHPICTYIEIGHHPEDNIFKLENSHFENGRGKSPYDPKLLTASL
  LIDGELYSGTAADFMGRDFAIFRTLGHHHPIRTEQHDSRWLNDPKFISAHLISESDNPED
  DKVYFFFRENAIDGEHSGKATHARIGQICKNDFGGHRSLVNKWTTFLKARLICSVPGPNG
  IDTHFDELQDVFLMNFKDPKNPVVYGVFTTSSNIFKGSAVCMYSMSDVRRVFLGPYAHRD
  GPNYQWVPYQGRVPYPRPGTCPSKTFGGFDSTKDLPDDVITFARSHPAMYNPVFPMNNRP
  IVIKTDVNYQFTQIVVDRVDAEDGQYDVMFIGTDVGTVLKVVSIPKETWYDLEEVLLEEM
  TVFREPTAISAMELSTKQQQLYIGSTAGVAQLPLHRCDIYGKACAECCLARDPYCAWDGS
  ACSRYFPTAKRRTRRQDIRNGDPLTHCSDLHHDNHHGHSPEERIIYGVENSSTFLECSPK
  SQRALVYWQFQRRNEERKEEIRVDDHIIRTDQGLLLRSLQQKDSGNYLCHAVEHGFIQTL
  LKVTLEVIDTEHLEELLHKDDDGDGSKTKEMSNSMTPSQKVWYRDFMQLINHPNLNTMDE
  FCEQVWKRDRKQRRQRPGHTPGNSNKWKHLQENKKGRNRRTHEFERAPRSV
• Function: Involved in the development of the olfactory system and in neuronal control of puberty. Induces the collapse and paralysis of neuronal growth cones. Could serve as a ligand that guides specific growth cones by a motility-inhibiting mechanism. Binds to the complex neuropilin-1/plexin-1.
• Tissue Specificity: Expressed in the dorsal root ganglia.
• KEGG Pathway: Axon guidance (hsa04360)
• Reactome Pathway:
  SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion (R-HSA-399955)
  CRMPs in Sema3A signaling (R-HSA-399956)
  Sema3A PAK dependent Axon repulsion (R-HSA-399954)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypogonadotropic hypogonadism 16 with or without anosmia	DISXRAPW	Strong	Autosomal dominant	[1]
Brugada syndrome	DISSGN0E	Supportive	Autosomal dominant	[2]
Kallmann syndrome	DISO3HDG	Supportive	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DTI-015	DMXZRW0	Approved	Semaphorin-3A (SEMA3A) affects the response to substance of DTI-015.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Semaphorin-3A (SEMA3A).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Semaphorin-3A (SEMA3A).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Semaphorin-3A (SEMA3A).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Semaphorin-3A (SEMA3A).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Semaphorin-3A (SEMA3A).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Semaphorin-3A (SEMA3A).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Semaphorin-3A (SEMA3A).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Semaphorin-3A (SEMA3A).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Semaphorin-3A (SEMA3A).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Semaphorin-3A (SEMA3A).	[13]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Semaphorin-3A (SEMA3A).	[14]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Semaphorin-3A (SEMA3A).	[15]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Semaphorin-3A (SEMA3A).	[16]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Semaphorin-3A (SEMA3A).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Semaphorin-3A (SEMA3A).	[18]
PD-0325901	DM27D4J	Phase 2	PD-0325901 decreases the expression of Semaphorin-3A (SEMA3A).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Semaphorin-3A (SEMA3A).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Semaphorin-3A (SEMA3A).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Semaphorin-3A (SEMA3A).	[23]

2 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-3A (SEMA3A).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Semaphorin-3A (SEMA3A).	[20]

References

• [1] SEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development. Hum Reprod. 2012 May;27(5):1460-5. doi: 10.1093/humrep/des022. Epub 2012 Mar 12.
• [2] Genetic interpretation and clinical translation of minor genes related to Brugada syndrome. Hum Mutat. 2019 Jun;40(6):749-764. doi: 10.1002/humu.23730. Epub 2019 Mar 29.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [14] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [15] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [16] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [17] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.
• [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] 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.
• [23] 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.
• [24] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.