Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8901H3)

• DOT Name: Semaphorin-4A (SEMA4A)
• Synonyms: Semaphorin-B; Sema B
• Gene Name: SEMA4A
• Related Disease:
  Adenocarcinoma
  Allergic asthma
  Asthma
  Atopic dermatitis
  Breast carcinoma
  Cone-rod dystrophy 2
  Disorder of orbital region
  Hepatocellular carcinoma
  HIV infectious disease
  Multiple sclerosis
  Osteoarthritis
  Pneumonia
  Pneumonitis
  Pulmonary fibrosis
  Rheumatoid arthritis
  Squamous cell carcinoma
  Blindness
  Cone-rod dystrophy
  Familial colorectal cancer type X
  Retinitis pigmentosa
  Arthritis
  Lynch syndrome
  Acne vulgaris
  Advanced cancer
  Breast cancer
  Bronchiolitis
  Cervical cancer
  Cervical carcinoma
  Cervical Intraepithelial neoplasia
  Cone-rod dystrophy 10
  Hereditary nonpolyposis colon cancer
  Lynch syndrome 1
  Lynch syndrome 2
  Metastatic malignant neoplasm
  Neoplasm
  Pulmonary disease
  Retinitis pigmentosa 35
  Sarcoidosis
  Systemic sclerosis
  Tuberculosis
• UniProt ID: SEM4A_HUMAN
• Pfam ID: PF01437 ; PF01403
• Sequence:
  MALPALGLDPWSLLGLFLFQLLQLLLPTTTAGGGGQGPMPRVRYYAGDERRALSFFHQKG
  LQDFDTLLLSGDGNTLYVGAREAILALDIQDPGVPRLKNMIPWPASDRKKSECAFKKKSN
  ETQCFNFIRVLVSYNVTHLYTCGTFAFSPACTFIELQDSYLLPISEDKVMEGKGQSPFDP
  AHKHTAVLVDGMLYSGTMNNFLGSEPILMRTLGSQPVLKTDNFLRWLHHDASFVAAIPST
  QVVYFFFEETASEFDFFERLHTSRVARVCKNDVGGEKLLQKKWTTFLKAQLLCTQPGQLP
  FNVIRHAVLLPADSPTAPHIYAVFTSQWQVGGTRSSAVCAFSLLDIERVFKGKYKELNKE
  TSRWTTYRGPETNPRPGSCSVGPSSDKALTFMKDHFLMDEQVVGTPLLVKSGVEYTRLAV
  ETAQGLDGHSHLVMYLGTTTGSLHKAVVSGDSSAHLVEEIQLFPDPEPVRNLQLAPTQGA
  VFVGFSGGVWRVPRANCSVYESCVDCVLARDPHCAWDPESRTCCLLSAPNLNSWKQDMER
  GNPEWACASGPMSRSLRPQSRPQIIKEVLAVPNSILELPCPHLSALASYYWSHGPAAVPE
  ASSTVYNGSLLLIVQDGVGGLYQCWATENGFSYPVISYWVDSQDQTLALDPELAGIPREH
  VKVPLTRVSGGAALAAQQSYWPHFVTVTVLFALVLSGALIILVASPLRALRARGKVQGCE
  TLRPGEKAPLSREQHLQSPKECRTSASDVDADNNCLGTEVA
• Function: Cell surface receptor for PLXNB1, PLXNB2, PLXNB3 and PLXND1 that plays an important role in cell-cell signaling. Regulates glutamatergic and GABAergic synapse development. Promotes the development of inhibitory synapses in a PLXNB1-dependent manner and promotes the development of excitatory synapses in a PLXNB2-dependent manner. Plays a role in priming antigen-specific T-cells, promotes differentiation of Th1 T-helper cells, and thereby contributes to adaptive immunity. Promotes phosphorylation of TIMD2. Inhibits angiogenesis. Promotes axon growth cone collapse. Inhibits axonal extension by providing local signals to specify territories inaccessible for growing axons.
• KEGG Pathway: Axon guidance (hsa04360)
• Reactome Pathway: Other semaphorin interactions (R-HSA-416700)

Molecular Interaction Atlas (MIA) of This DOT

40 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[1]
Allergic asthma	DISHF0H3	Strong	Biomarker	[2]
Asthma	DISW9QNS	Strong	Biomarker	[3]
Atopic dermatitis	DISTCP41	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Cone-rod dystrophy 2	DISX2RWY	Strong	Genetic Variation	[5]
Disorder of orbital region	DISH0ECJ	Strong	Genetic Variation	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
HIV infectious disease	DISO97HC	Strong	Altered Expression	[7]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[8]
Osteoarthritis	DIS05URM	Strong	Biomarker	[9]
Pneumonia	DIS8EF3M	Strong	Biomarker	[2]
Pneumonitis	DIS88E0K	Strong	Biomarker	[2]
Pulmonary fibrosis	DISQKVLA	Strong	Altered Expression	[10]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[11]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[1]
Blindness	DISTIM10	moderate	Genetic Variation	[12]
Cone-rod dystrophy	DISY9RWN	Supportive	Autosomal dominant	[5]
Familial colorectal cancer type X	DISEBNIA	Supportive	Autosomal dominant	[13]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[14]
Arthritis	DIST1YEL	Disputed	Biomarker	[15]
Lynch syndrome	DIS3IW5F	Disputed	Autosomal dominant	[16]
Acne vulgaris	DISKW8PI	Limited	Biomarker	[17]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[6]
Breast cancer	DIS7DPX1	Limited	Biomarker	[4]
Bronchiolitis	DISEE9BG	Limited	Biomarker	[3]
Cervical cancer	DISFSHPF	Limited	Altered Expression	[18]
Cervical carcinoma	DIST4S00	Limited	Altered Expression	[18]
Cervical Intraepithelial neoplasia	DISXP757	Limited	Biomarker	[18]
Cone-rod dystrophy 10	DISDWCBG	Limited	Unknown	[19]
Hereditary nonpolyposis colon cancer	DISPA49R	Limited	Biomarker	[20]
Lynch syndrome 1	DISSABLZ	Limited	Biomarker	[20]
Lynch syndrome 2	DISRLYU1	Limited	Biomarker	[20]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[6]
Neoplasm	DISZKGEW	Limited	Altered Expression	[4]
Pulmonary disease	DIS6060I	Limited	Biomarker	[17]
Retinitis pigmentosa 35	DISKQHGW	Limited	Autosomal recessive	[12]
Sarcoidosis	DISE5B8Z	Limited	Biomarker	[17]
Systemic sclerosis	DISF44L6	Limited	Biomarker	[21]
Tuberculosis	DIS2YIMD	Limited	Biomarker	[17]

2 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-4A (SEMA4A).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Semaphorin-4A (SEMA4A).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Semaphorin-4A (SEMA4A).	[23]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Semaphorin-4A (SEMA4A).	[24]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Semaphorin-4A (SEMA4A).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Semaphorin-4A (SEMA4A).	[27]

References

• [1] Prognostic value of nuclear DNA content and expression of the ras oncogene product in lung cancer.Cancer Res. 1991 Dec 1;51(23 Pt 1):6346-50.
• [2] An inhibitory role for Sema4A in antigen-specific allergic asthma.J Clin Immunol. 2013 Jan;33(1):200-9. doi: 10.1007/s10875-012-9798-5. Epub 2012 Sep 25.
• [3] Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a-mediated T reg expansion.J Exp Med. 2018 Feb 5;215(2):537-557. doi: 10.1084/jem.20170298. Epub 2017 Dec 22.
• [4] Sema4A Responds to Hypoxia and Is Involved in Breast Cancer Progression.Biol Pharm Bull. 2018 Dec 1;41(12):1791-1796. doi: 10.1248/bpb.b18-00423. Epub 2018 Sep 28.
• [5] Identification of novel mutations in the SEMA4A gene associated with retinal degenerative diseases. J Med Genet. 2006 Apr;43(4):378-81. doi: 10.1136/jmg.2005.035055. Epub 2005 Sep 30.
• [6] Neuroimmune Semaphorin 4A in Cancer Angiogenesis and Inflammation: A Promoter or a Suppressor?.Int J Mol Sci. 2018 Dec 30;20(1):124. doi: 10.3390/ijms20010124.
• [7] Semaphorin4A causes loss of mature oligodendrocytes and demyelination in vivo.J Neuroinflammation. 2019 Feb 8;16(1):28. doi: 10.1186/s12974-019-1420-9.
• [8] Beneficial effects of fingolimod in MS patients with high serum Sema4A levels.PLoS One. 2018 Mar 8;13(3):e0193986. doi: 10.1371/journal.pone.0193986. eCollection 2018.
• [9] Semaphorin 4A acts in a feed-forward loop with NF-B pathway to exacerbate catabolic effect of IL-1 on chondrocytes.Int Immunopharmacol. 2019 Apr;69:88-94. doi: 10.1016/j.intimp.2019.01.006. Epub 2019 Jan 25.
• [10] Semaphorin 4A enhances lung fibrosis through activation of Akt via PlexinD1 receptor.J Biosci. 2015 Dec;40(5):855-62. doi: 10.1007/s12038-015-9566-9.
• [11] Expression of Semaphorin 4A and its potential role in rheumatoid arthritis.Arthritis Res Ther. 2015 Aug 25;17(1):227. doi: 10.1186/s13075-015-0734-y.
• [12] On variants and disease-causing mutations: Case studies of a SEMA4A variant identified in inherited blindness. Ophthalmic Genet. 2018 Jan-Feb;39(1):144-146. doi: 10.1080/13816810.2017.1354384. Epub 2017 Aug 14.
• [13] Germline variants in the SEMA4A gene predispose to familial colorectal cancer type X. Nat Commun. 2014 Oct 13;5:5191. doi: 10.1038/ncomms6191.
• [14] Nonsyndromic Retinitis Pigmentosa Overview. 2000 Aug 4 [updated 2023 Apr 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [15] Semaphorin 4A as novel regulator and promising therapeutic target in rheumatoid arthritis.Arthritis Res Ther. 2015 Nov 6;17:313. doi: 10.1186/s13075-015-0846-4.
• [16] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [17] Proliferative response of peripheral blood mononuclear cells and levels of antibody to recombinant protein from Propionibacterium acnes DNA expression library in Japanese patients with sarcoidosis.Sarcoidosis Vasc Diffuse Lung Dis. 2000 Oct;17(3):256-65.
• [18] Ras oncogene expression and progression in intraepithelial neoplasia of the uterine cervix.Cancer. 1990 Jul 15;66(2):295-301. doi: 10.1002/1097-0142(19900715)66:2<295::aid-cncr2820660217>3.0.co;2-e.
• [19] Severe retinal degeneration associated with disruption of semaphorin 4A. Invest Ophthalmol Vis Sci. 2004 Aug;45(8):2767-77. doi: 10.1167/iovs.04-0020.
• [20] Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis. Am J Hum Genet. 2016 Aug 4;99(2):337-51. doi: 10.1016/j.ajhg.2016.06.015. Epub 2016 Jul 28.
• [21] Induction of Inflammation and Fibrosis by Semaphorin 4A in Systemic Sclerosis.Arthritis Rheumatol. 2019 Oct;71(10):1711-1722. doi: 10.1002/art.40915. Epub 2019 Aug 27.
• [22] 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.
• [23] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [24] 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.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] 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.
• [27] 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.