Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3GBVHL)

• DOT Name: Disintegrin and metalloproteinase domain-containing protein 28 (ADAM28)
• Synonyms: ADAM 28; EC 3.4.24.-; Epididymal metalloproteinase-like, disintegrin-like, and cysteine-rich protein II; eMDC II; Metalloproteinase-like, disintegrin-like, and cysteine-rich protein L; MDC-L
• Gene Name: ADAM28
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Breast carcinoma
  Breast neoplasm
  Clear cell renal carcinoma
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Lung cancer
  Lung neoplasm
  Metastatic malignant neoplasm
  Non-insulin dependent diabetes
  Obesity
  Osteoarthritis
  Pancreatic cancer
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Renal cell carcinoma
  Carcinoma
  Lung carcinoma
  Non-small-cell lung cancer
  Small lymphocytic lymphoma
  Adult lymphoma
  Colorectal carcinoma
  Lymphoma
  Pediatric lymphoma
• UniProt ID: ADA28_HUMAN
• EC Number: 3.4.24.-
• Pfam ID: PF08516 ; PF00200 ; PF01562 ; PF01421
• Sequence:
  MLQGLLPVSLLLSVAVSAIKELPGVKKYEVVYPIRLHPLHKREAKEPEQQEQFETELKYK
  MTINGKIAVLYLKKNKNLLAPGYTETYYNSTGKEITTSPQIMDDCYYQGHILNEKVSDAS
  ISTCRGLRGYFSQGDQRYFIEPLSPIHRDGQEHALFKYNPDEKNYDSTCGMDGVLWAHDL
  QQNIALPATKLVKLKDRKVQEHEKYIEYYLVLDNGEFKRYNENQDEIRKRVFEMANYVNM
  LYKKLNTHVALVGMEIWTDKDKIKITPNASFTLENFSKWRGSVLSRRKRHDIAQLITATE
  LAGTTVGLAFMSTMCSPYSVGVVQDHSDNLLRVAGTMAHEMGHNFGMFHDDYSCKCPSTI
  CVMDKALSFYIPTDFSSCSRLSYDKFFEDKLSNCLFNAPLPTDIISTPICGNQLVEMGED
  CDCGTSEECTNICCDAKTCKIKATFQCALGECCEKCQFKKAGMVCRPAKDECDLPEMCNG
  KSGNCPDDRFQVNGFPCHHGKGHCLMGTCPTLQEQCTELWGPGTEVADKSCYNRNEGGSK
  YGYCRRVDDTLIPCKANDTMCGKLFCQGGSDNLPWKGRIVTFLTCKTFDPEDTSQEIGMV
  ANGTKCGDNKVCINAECVDIEKAYKSTNCSSKCKGHAVCDHELQCQCEEGWIPPDCDDSS
  VVFHFSIVVGVLFPMAVIFVVVAMVIRHQSSREKQKKDQRPLSTTGTRPHKQKRKPQMVK
  AVQPQEMSQMKPHVYDLPVEGNEPPASFHKDTNALPPTVFKDNPVSTPKDSNPKA
• Function: May play a role in the adhesive and proteolytic events that occur during lymphocyte emigration or may function in ectodomain shedding of lymphocyte surface target proteins, such as FASL and CD40L. May be involved in sperm maturation.
• Tissue Specificity: Expressed predominantly in secondary lymphoid tissues, such as lymph node, spleen, small intestine, stomach, colon, appendix and trachea. The lymphocyte population is responsible for expression of this protein in these tissues. Isoform 2 is expressed preferentially in spleen.

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[4]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[5]
Lung cancer	DISCM4YA	Strong	Biomarker	[6]
Lung neoplasm	DISVARNB	Strong	Biomarker	[7]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[8]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[9]
Obesity	DIS47Y1K	Strong	Altered Expression	[9]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[10]
Pancreatic cancer	DISJC981	Strong	Biomarker	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[11]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[12]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[11]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[3]
Carcinoma	DISH9F1N	moderate	Biomarker	[13]
Lung carcinoma	DISTR26C	moderate	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	moderate	Biomarker	[5]
Small lymphocytic lymphoma	DIS30POX	moderate	Biomarker	[14]
Adult lymphoma	DISK8IZR	Limited	Biomarker	[15]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[16]
Lymphoma	DISN6V4S	Limited	Biomarker	[15]
Pediatric lymphoma	DIS51BK2	Limited	Biomarker	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Disintegrin and metalloproteinase domain-containing protein 28 (ADAM28).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Disintegrin and metalloproteinase domain-containing protein 28 (ADAM28).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Disintegrin and metalloproteinase domain-containing protein 28 (ADAM28).	[19]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Disintegrin and metalloproteinase domain-containing protein 28 (ADAM28).	[20]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Disintegrin and metalloproteinase domain-containing protein 28 (ADAM28).	[21]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Disintegrin and metalloproteinase domain-containing protein 28 (ADAM28).	[22]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Disintegrin and metalloproteinase domain-containing protein 28 (ADAM28).	[23]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Disintegrin and metalloproteinase domain-containing protein 28 (ADAM28).	[24]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Disintegrin and metalloproteinase domain-containing protein 28 (ADAM28).	[25]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Disintegrin and metalloproteinase domain-containing protein 28 (ADAM28).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Disintegrin and metalloproteinase domain-containing protein 28 (ADAM28).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Disintegrin and metalloproteinase domain-containing protein 28 (ADAM28).	[28]

References

• [1] ADAM28 promotes tumor growth and dissemination of acute myeloid leukemia through IGFBP-3 degradation and IGF-I-induced cell proliferation.Cancer Lett. 2019 Feb 1;442:193-201. doi: 10.1016/j.canlet.2018.10.028. Epub 2018 Oct 26.
• [2] Oncogenic ADAM28 induces gemcitabine resistance and predicts a poor prognosis in pancreatic cancer.World J Gastroenterol. 2019 Oct 7;25(37):5590-5603. doi: 10.3748/wjg.v25.i37.5590.
• [3] Effect of ADAM28 on carcinoma cell metastasis by cleavage of von Willebrand factor.J Natl Cancer Inst. 2012 Jun 20;104(12):906-22. doi: 10.1093/jnci/djs232. Epub 2012 May 25.
• [4] Epigenetic silencing of the adhesion molecule ADAM23 is highly frequent in breast tumors.Oncogene. 2004 Feb 19;23(7):1481-8. doi: 10.1038/sj.onc.1207263.
• [5] Selective Inhibition of ADAM28 Suppresses Lung Carcinoma Cell Growth and Metastasis.Mol Cancer Ther. 2018 Nov;17(11):2427-2438. doi: 10.1158/1535-7163.MCT-17-1198. Epub 2018 Sep 6.
• [6] Differential expressions of matrix metalloproteinases, a disintegrin and metalloproteinases, and a disintegrin and metalloproteinases with thrombospondin motifs and their endogenous inhibitors among histologic subtypes of lung cancers.Anticancer Agents Med Chem. 2012 Sep;12(7):744-52. doi: 10.2174/187152012802650156.
• [7] ADAM28: a potential oncogene involved in asbestos-related lung adenocarcinomas.Genes Chromosomes Cancer. 2010 Aug;49(8):688-98. doi: 10.1002/gcc.20779.
• [8] Adamalysines as Biomarkers and a Potential Target of Therapy in Colorectal Cancer Patients: Preliminary Results.Dis Markers. 2019 Sep 2;2019:5035234. doi: 10.1155/2019/5035234. eCollection 2019.
• [9] The Metalloproteinase ADAM28 Promotes Metabolic Dysfunction in Mice.Int J Mol Sci. 2017 Apr 21;18(4):884. doi: 10.3390/ijms18040884.
• [10] All-trans retinoic acid-induced ADAM28 degrades proteoglycans in human chondrocytes.Biochem Biophys Res Commun. 2009 Aug 21;386(2):294-9. doi: 10.1016/j.bbrc.2009.06.052. Epub 2009 Jun 13.
• [11] Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets.Nat Genet. 2018 May;50(5):682-692. doi: 10.1038/s41588-018-0086-z. Epub 2018 Apr 16.
• [12] Overexpression and knock-down studies highlight that a disintegrin and metalloproteinase 28 controls proliferation and migration in human prostate cancer.Medicine (Baltimore). 2016 Oct;95(40):e5085. doi: 10.1097/MD.0000000000005085.
• [13] SOX4, an epithelial-mesenchymal transition inducer, transactivates ADAM28 gene expression and co-localizes with ADAM28 at the invasive front of human breast and lung carcinomas.Pathol Int. 2018 Jun 7. doi: 10.1111/pin.12685. Online ahead of print.
• [14] Ectodomain shedding of CD200 from the B-CLL cell surface is regulated by ADAM28 expression.Leuk Res. 2013 Jul;37(7):816-21. doi: 10.1016/j.leukres.2013.04.014. Epub 2013 May 1.
• [15] The lymphocyte metalloprotease MDC-L (ADAM 28) is a ligand for the integrin alpha4beta1.J Biol Chem. 2002 Feb 1;277(5):3784-92. doi: 10.1074/jbc.M109538200. Epub 2001 Nov 27.
• [16] MiR-198 affects the proliferation and apoptosis of colorectal cancer through regulation of ADAM28/JAK-STAT signaling pathway.Eur Rev Med Pharmacol Sci. 2019 Feb;23(4):1487-1493. doi: 10.26355/eurrev_201902_17106.
• [17] 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.
• [18] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [19] 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.
• [20] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [21] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [22] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [23] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [24] 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.
• [25] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [26] 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.
• [27] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [28] 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.