Details of Drug Off-Target (DOT)

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

DOT Name	Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12)
Synonyms	ADAM 12; EC 3.4.24.-; Meltrin-alpha
Gene Name	ADAM12
Related Disease	Neoplasm ( ) Advanced cancer ( ) Alzheimer disease ( ) Arteriosclerosis ( ) Astrocytoma ( ) Atherosclerosis ( ) Attention deficit hyperactivity disorder ( ) Benign neoplasm ( ) Brain neoplasm ( ) Breast cancer ( ) Breast carcinoma ( ) Carcinoma ( ) Carcinoma of esophagus ( ) Chromosomal disorder ( ) Esophageal cancer ( ) Esophageal squamous cell carcinoma ( ) Fetal growth restriction ( ) Gastric cancer ( ) Glioblastoma multiforme ( ) Head and neck cancer ( ) Head and neck carcinoma ( ) Head-neck squamous cell carcinoma ( ) Liver cancer ( ) Liver cirrhosis ( ) Lung neoplasm ( ) Lymphoma, non-Hodgkin, familial ( ) Matthew-Wood syndrome ( ) Neoplasm of esophagus ( ) Non-hodgkin lymphoma ( ) Obesity ( ) Pancreatic cancer ( ) Schizophrenia ( ) Skin cancer ( ) Squamous cell carcinoma ( ) Stomach cancer ( ) Knee osteoarthritis ( ) Melanoma ( ) Metastatic malignant neoplasm ( ) Small-cell lung cancer ( ) Triple negative breast cancer ( ) Neuroblastoma ( ) Adenocarcinoma ( ) Adult glioblastoma ( ) Asthma ( ) Invasive ductal breast carcinoma ( ) Lung adenocarcinoma ( ) Urinary bladder cancer ( )
UniProt ID	ADA12_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
EC Number	3.4.24.-
Pfam ID	PF08516 ; PF00200 ; PF01562 ; PF01421
Sequence	MAARPLPVSPARALLLALAGALLAPCEARGVSLWNQGRADEVVSASVGSGDLWIPVKSFD SKNHPEVLNIRLQRESKELIINLERNEGLIASSFTETHYLQDGTDVSLARNYTVILGHCY YHGHVRGYSDSAVSLSTCSGLRGLIVFENESYVLEPMKSATNRYKLFPAKKLKSVRGSCG SHHNTPNLAAKNVFPPPSQTWARRHKRETLKATKYVELVIVADNREFQRQGKDLEKVKQR LIEIANHVDKFYRPLNIRIVLVGVEVWNDMDKCSVSQDPFTSLHEFLDWRKMKLLPRKSH DNAQLVSGVYFQGTTIGMAPIMSMCTADQSGGIVMDHSDNPLGAAVTLAHELGHNFGMNH DTLDRGCSCQMAVEKGGCIMNASTGYPFPMVFSSCSRKDLETSLEKGMGVCLFNLPEVRE SFGGQKCGNRFVEEGEECDCGEPEECMNRCCNATTCTLKPDAVCAHGLCCEDCQLKPAGT ACRDSSNSCDLPEFCTGASPHCPANVYLHDGHSCQDVDGYCYNGICQTHEQQCVTLWGPG AKPAPGICFERVNSAGDPYGNCGKVSKSSFAKCEMRDAKCGKIQCQGGASRPVIGTNAVS IETNIPLQQGGRILCRGTHVYLGDDMPDPGLVLAGTKCADGKICLNRQCQNISVFGVHEC AMQCHGRGVCNNRKNCHCEAHWAPPFCDKFGFGGSTDSGPIRQADNQGLTIGILVTILCL LAAGFVVYLKRKTLIRLLFTNKKTTIEKLRCVRPSRPPRGFQPCQAHLGHLGKGLMRKPP DSYPPKDNPRRLLQCQNVDISRPLNGLNVPQPQSTQRVLPPLHRAPRAPSVPARPLPAKP ALRQAQGTCKPNPPQKPLPADPLARTTRLTHALARTPGQWETGLRLAPLRPAPQYPHQVP RSTHTAYIK
Function	Involved in skeletal muscle regeneration, specifically at the onset of cell fusion. Also involved in macrophage-derived giant cells (MGC) and osteoclast formation from mononuclear precursors.
Tissue Specificity	Isoform 1 is expressed in placenta and skeletal, cardiac, and smooth muscle. Isoform 2 seems to be expressed only in placenta or in embryo and fetus. Both forms were expressed in some tumor cells lines. Not detected in brain, lung, liver, kidney or pancreas.
Reactome Pathway	Invadopodia formation (R-HSA-8941237 ) Signaling by EGFR (R-HSA-177929 )

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Astrocytoma	DISL3V18	Strong	Biomarker	[5]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[4]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[6]
Benign neoplasm	DISDUXAD	Strong	Altered Expression	[7]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[8]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[8]
Carcinoma	DISH9F1N	Strong	Altered Expression	[9]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[10]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[11]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[10]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[10]
Fetal growth restriction	DIS5WEJ5	Strong	Biomarker	[12]
Gastric cancer	DISXGOUK	Strong	Biomarker	[13]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[14]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[15]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[15]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[15]
Liver cancer	DISDE4BI	Strong	Altered Expression	[9]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[16]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[17]
Lymphoma, non-Hodgkin, familial	DISCXYIZ	Strong	Altered Expression	[18]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[19]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[10]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Altered Expression	[18]
Obesity	DIS47Y1K	Strong	Genetic Variation	[20]
Pancreatic cancer	DISJC981	Strong	Biomarker	[19]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[21]
Skin cancer	DISTM18U	Strong	Altered Expression	[22]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[22]
Stomach cancer	DISKIJSX	Strong	Biomarker	[13]
Knee osteoarthritis	DISLSNBJ	moderate	Genetic Variation	[23]
Melanoma	DIS1RRCY	moderate	Genetic Variation	[24]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[1]
Small-cell lung cancer	DISK3LZD	moderate	Altered Expression	[25]
Triple negative breast cancer	DISAMG6N	moderate	Biomarker	[26]
Neuroblastoma	DISVZBI4	Disputed	Biomarker	[27]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[28]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[14]
Asthma	DISW9QNS	Limited	Biomarker	[29]
Invasive ductal breast carcinoma	DIS43J58	Limited	Altered Expression	[30]
Lung adenocarcinoma	DISD51WR	Limited	Biomarker	[1]
Urinary bladder cancer	DISDV4T7	Limited	Altered Expression	[31]
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⏷ Show the Full List of 47 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12) increases the Metabolic disorder ADR of Chlorothiazide.	[47]
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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 Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12).	[32]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12).	[42]
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15 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12).	[33]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12).	[34]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12).	[35]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12).	[36]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12).	[37]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12).	[38]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12).	[39]
Liothyronine	DM6IR3P	Approved	Liothyronine increases the expression of Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12).	[40]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone decreases the expression of Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12).	[41]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12).	[38]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12).	[38]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12).	[43]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12).	[44]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12).	[45]
Forskolin	DM6ITNG	Investigative	Forskolin decreases the expression of Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12).	[46]
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⏷ Show the Full List of 15 Drug(s)

References

1	Long noncoding RNA CAR10 promotes lung adenocarcinoma metastasis via miR-203/30/SNAI axis.Oncogene. 2019 Apr;38(16):3061-3076. doi: 10.1038/s41388-018-0645-x. Epub 2019 Jan 7.
2	Identification of ADAM12 as a Novel Basigin Sheddase.Int J Mol Sci. 2019 Apr 22;20(8):1957. doi: 10.3390/ijms20081957.
3	A study of the association between the ADAM12 and SH3PXD2A (SH3MD1) genes and Alzheimer's disease.Neurosci Lett. 2010 Jan 1;468(1):1-2. doi: 10.1016/j.neulet.2009.10.040. Epub 2009 Oct 22.
4	Expression and cellular localization of metalloproteases ADAMs in high graded carotid artery lesions.Scand J Clin Lab Invest. 2012 Dec;72(8):648-56. doi: 10.3109/00365513.2012.734394. Epub 2012 Oct 29.
5	ADAM 12: a putative marker of oligodendrogliomas?.Dis Markers. 2013;34(2):81-91. doi: 10.3233/DMA-120953.
6	Genome-wide analyses of aggressiveness in attention-deficit hyperactivity disorder.Am J Med Genet B Neuropsychiatr Genet. 2016 Jul;171(5):733-47. doi: 10.1002/ajmg.b.32434. Epub 2016 Mar 29.
7	ADAM12 and ADAM17 gene expression in laser-capture microdissected and non-microdissected breast tumors.Pathol Oncol Res. 2011 Jun;17(2):375-85. doi: 10.1007/s12253-010-9336-9. Epub 2011 Jan 16.
8	Proteomic screening identifies the zonula occludens protein ZO-1 as a new partner for ADAM12 in invadopodia-like structures.Oncotarget. 2018 Apr 20;9(30):21366-21382. doi: 10.18632/oncotarget.25106. eCollection 2018 Apr 20.
9	ADAM12 in human liver cancers: TGF-beta-regulated expression in stellate cells is associated with matrix remodeling.Hepatology. 2003 May;37(5):1056-66. doi: 10.1053/jhep.2003.50205.
10	An ADAM12 and FAK positive feedback loop amplifies the interaction signal of tumor cells with extracellular matrix to promote esophageal cancer metastasis.Cancer Lett. 2018 May 28;422:118-128. doi: 10.1016/j.canlet.2018.02.031. Epub 2018 Feb 21.
11	ADAM12 as a marker of trisomy 18 in the first and second trimester of pregnancy.J Matern Fetal Neonatal Med. 2007 Sep;20(9):645-50. doi: 10.1080/14767050701483389.
12	First trimester maternal serum analytes and second trimester uterine artery Doppler in the prediction of preeclampsia and fetal growth restriction.Taiwan J Obstet Gynecol. 2017 Jun;56(3):358-361. doi: 10.1016/j.tjog.2017.01.009.
13	The disintegrin-metalloproteinases ADAM9, ADAM12, and ADAM15 are upregulated in gastric cancer.Int J Oncol. 2005 Jan;26(1):17-24.
14	ADAR2/miR-589-3p axis controls glioblastoma cell migration/invasion.Nucleic Acids Res. 2018 Feb 28;46(4):2045-2059. doi: 10.1093/nar/gkx1257.
15	A positive feedback loop between HER2 and ADAM12 in human head and neck cancer cells increases migration and invasion.Oncogene. 2012 Jun 7;31(23):2888-98. doi: 10.1038/onc.2011.460. Epub 2011 Oct 10.
16	Involvement of the serine/threonine p70S6 kinase in TGF-beta1-induced ADAM12 expression in cultured human hepatic stellate cells.J Hepatol. 2005 Dec;43(6):1038-44. doi: 10.1016/j.jhep.2005.05.025. Epub 2005 Jun 29.
17	Expression of a disintegrin and metalloprotease (ADAM and ADAMTS) enzymes in human non-small-cell lung carcinomas (NSCLC).Br J Cancer. 2006 Mar 13;94(5):724-30. doi: 10.1038/sj.bjc.6602990.
18	Upregulation of ADAM12 contributes to accelerated cell proliferation and cell adhesion-mediated drug resistance (CAM-DR) in Non-Hodgkin's Lymphoma.Hematology. 2017 Oct;22(9):527-535. doi: 10.1080/10245332.2017.1312205. Epub 2017 Apr 10.
19	ADAM12 is a circulating marker for stromal activation in pancreatic cancer and predicts response to chemotherapy.Oncogenesis. 2018 Nov 16;7(11):87. doi: 10.1038/s41389-018-0096-9.
20	Large-scale in silico mapping of complex quantitative traits in inbred mice.PLoS One. 2007 Jul 25;2(7):e651. doi: 10.1371/journal.pone.0000651.
21	Reduced density of ADAM 12-immunoreactive oligodendrocytes in the anterior cingulate white matter of patients with schizophrenia.World J Biol Psychiatry. 2010 Apr;11(3):556-66. doi: 10.3109/15622970903497936.
22	Erbb2 up-regulation of ADAM12 expression accelerates skin cancer progression.Mol Carcinog. 2015 Oct;54(10):1026-36. doi: 10.1002/mc.22171. Epub 2014 May 5.
23	Association between ADAM12 Single-Nucleotide Polymorphisms and Knee Osteoarthritis: A Meta-Analysis.Biomed Res Int. 2017;2017:5398181. doi: 10.1155/2017/5398181. Epub 2017 Aug 8.
24	Molecular profiling of ADAM12 and ADAM17 genes in human malignant melanoma.Pathol Oncol Res. 2013 Oct;19(4):755-62. doi: 10.1007/s12253-013-9639-8. Epub 2013 May 6.
25	Expression of ADAM12 is regulated by E2F1 in small cell lung cancer.Oncol Rep. 2015 Dec;34(6):3231-7. doi: 10.3892/or.2015.4317.
26	Phenotypic diversity of breast cancer-related mutations in metalloproteinase-disintegrin ADAM12.PLoS One. 2014 Mar 20;9(3):e92536. doi: 10.1371/journal.pone.0092536. eCollection 2014.
27	Carvacrol Depends on Heme Oxygenase-1 (HO-1) to Exert Antioxidant, Anti-inflammatory, and Mitochondria-Related Protection in the Human Neuroblastoma SH-SY5Y Cells Line Exposed to Hydrogen Peroxide.Neurochem Res. 2019 Apr;44(4):884-896. doi: 10.1007/s11064-019-02724-5. Epub 2019 Jan 16.
28	Unlike pancreatic cancer cells pancreatic cancer associated fibroblasts display minimal gene induction after 5-aza-2'-deoxycytidine.PLoS One. 2012;7(9):e43456. doi: 10.1371/journal.pone.0043456. Epub 2012 Sep 11.
29	ADAM33 and ADAM12 genetic polymorphisms and their expression in Egyptian children with asthma.Ann Allergy Asthma Immunol. 2016 Jan;116(1):31-6. doi: 10.1016/j.anai.2015.10.013. Epub 2015 Nov 6.
30	ADAM12 is expressed in the tumour vasculature and mediates ectodomain shedding of several membrane-anchored endothelial proteins.Biochem J. 2013 May 15;452(1):97-109. doi: 10.1042/BJ20121558.
31	Epigenetic regulation by Z-DNA silencer function controls cancer-associated ADAM-12 expression in breast cancer: cross-talk between MeCP2 and NF1 transcription factor family.Cancer Res. 2013 Jan 15;73(2):736-44. doi: 10.1158/0008-5472.CAN-12-2601. Epub 2012 Nov 7.
32	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.
33	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.
34	Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
35	Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
36	Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
37	Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
38	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.
39	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.
40	Monitoring of deiodinase deficiency based on transcriptomic responses in SH-SY5Y cells. Arch Toxicol. 2013 Jun;87(6):1103-13. doi: 10.1007/s00204-013-1018-4. Epub 2013 Feb 10.
41	Ultradian cortisol pulsatility encodes a distinct, biologically important signal. PLoS One. 2011 Jan 18;6(1):e15766.
42	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.
43	Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
44	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.
45	Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
46	Drug development for ovarian hyper-stimulation and anti-cancer treatment: blocking of gonadotropin signaling for epiregulin and amphiregulin biosynthesis. Biochem Pharmacol. 2004 Sep 15;68(6):989-96. doi: 10.1016/j.bcp.2004.05.027.
47	Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.