Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT452ZDC)

• DOT Name: Disintegrin and metalloproteinase domain-containing protein 22 (ADAM22)
• Synonyms: ADAM 22; Metalloproteinase-disintegrin ADAM22-3; Metalloproteinase-like, disintegrin-like, and cysteine-rich protein 2
• Gene Name: ADAM22
• Related Disease:
  Epilepsy
  Glioma
  Neoplasm
  Autosomal dominant epilepsy with auditory features
  Carotid stenosis
  Epilepsy, familial temporal lobe, 1
  Hypertrophic cardiomyopathy
  Non-small-cell lung cancer
  Obstructive sleep apnea
  Developmental and epileptic encephalopathy, 61
  Breast cancer
  Breast carcinoma
• UniProt ID: ADA22_HUMAN
• PDB ID: 3G5C; 5Y2Z; 5Y31; 7CQF
• Pfam ID: PF08516 ; PF00200 ; PF07974 ; PF01562 ; PF01421
• Sequence:
  MQAAVAVSVPFLLLCVLGTCPPARCGQAGDASLMELEKRKENRFVERQSIVPLRLIYRSG
  GEDESRHDALDTRVRGDLGGPQLTHVDQASFQVDAFGTSFILDVVLNHDLLSSEYIERHI
  EHGGKTVEVKGGEHCYYQGHIRGNPDSFVALSTCHGLHGMFYDGNHTYLIEPEENDTTQE
  DFHFHSVYKSRLFEFSLDDLPSEFQQVNITPSKFILKPRPKRSKRQLRRYPRNVEEETKY
  IELMIVNDHLMFKKHRLSVVHTNTYAKSVVNMADLIYKDQLKTRIVLVAMETWATDNKFA
  ISENPLITLREFMKYRRDFIKEKSDAVHLFSGSQFESSRSGAAYIGGICSLLKGGGVNEF
  GKTDLMAVTLAQSLAHNIGIISDKRKLASGECKCEDTWSGCIMGDTGYYLPKKFTQCNIE
  EYHDFLNSGGGACLFNKPSKLLDPPECGNGFIETGEECDCGTPAECVLEGAECCKKCTLT
  QDSQCSDGLCCKKCKFQPMGTVCREAVNDCDIRETCSGNSSQCAPNIHKMDGYSCDGVQG
  ICFGGRCKTRDRQCKYIWGQKVTASDKYCYEKLNIEGTEKGNCGKDKDTWIQCNKRDVLC
  GYLLCTNIGNIPRLGELDGEITSTLVVQQGRTLNCSGGHVKLEEDVDLGYVEDGTPCGPQ
  MMCLEHRCLPVASFNFSTCLSSKEGTICSGNGVCSNELKCVCNRHWIGSDCNTYFPHNDD
  AKTGITLSGNGVAGTNIIIGIIAGTILVLALILGITAWGYKNYREQRQLPQGDYVKKPGD
  GDSFYSDIPPGVSTNSASSSKKRSNGLSHSWSERIPDTKHISDICENGRPRSNSWQGNLG
  GNKKKIRGKRFRPRSNSTETLSPAKSPSSSTGSIASSRKYPYPMPPLPDEDKKVNRQSAR
  LWETSI
• Function: Probable ligand for integrin in the brain. This is a non catalytic metalloprotease-like protein. Involved in regulation of cell adhesion and spreading and in inhibition of cell proliferation. Neuronal receptor for LGI1.
• Tissue Specificity: Highly expressed in the brain and in some high-grade but not low-grade gliomas. Detected slightly or not at all in other tissues.
• Reactome Pathway: LGI-ADAM interactions (R-HSA-5682910)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Definitive	Genetic Variation	[1]
Glioma	DIS5RPEH	Definitive	Altered Expression	[2]
Neoplasm	DISZKGEW	Definitive	Biomarker	[3]
Autosomal dominant epilepsy with auditory features	DISFZN2O	Strong	Genetic Variation	[4]
Carotid stenosis	DISZA8D0	Strong	Altered Expression	[5]
Epilepsy, familial temporal lobe, 1	DISTRYUX	Strong	Biomarker	[6]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Altered Expression	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[8]
Obstructive sleep apnea	DIS0SVD1	Strong	Genetic Variation	[9]
Developmental and epileptic encephalopathy, 61	DIS18LW2	Moderate	Autosomal recessive	[10]
Breast cancer	DIS7DPX1	Limited	Biomarker	[11]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[11]

13 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 Disintegrin and metalloproteinase domain-containing protein 22 (ADAM22).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Disintegrin and metalloproteinase domain-containing protein 22 (ADAM22).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Disintegrin and metalloproteinase domain-containing protein 22 (ADAM22).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Disintegrin and metalloproteinase domain-containing protein 22 (ADAM22).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Disintegrin and metalloproteinase domain-containing protein 22 (ADAM22).	[16]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Disintegrin and metalloproteinase domain-containing protein 22 (ADAM22).	[16]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Disintegrin and metalloproteinase domain-containing protein 22 (ADAM22).	[17]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Disintegrin and metalloproteinase domain-containing protein 22 (ADAM22).	[18]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Disintegrin and metalloproteinase domain-containing protein 22 (ADAM22).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Disintegrin and metalloproteinase domain-containing protein 22 (ADAM22).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Disintegrin and metalloproteinase domain-containing protein 22 (ADAM22).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Disintegrin and metalloproteinase domain-containing protein 22 (ADAM22).	[19]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Disintegrin and metalloproteinase domain-containing protein 22 (ADAM22).	[22]

References

• [1] Structural basis of epilepsy-related ligand-receptor complex LGI1-ADAM22.Nat Commun. 2018 Apr 18;9(1):1546. doi: 10.1038/s41467-018-03947-w.
• [2] Leucine-rich glioma inactivated 3: integrative analyses support its prognostic role in glioma.Onco Targets Ther. 2017 May 24;10:2721-2728. doi: 10.2147/OTT.S138912. eCollection 2017.
• [3] Global characterization of the SRC-1 transcriptome identifies ADAM22 as an ER-independent mediator of endocrine-resistant breast cancer.Cancer Res. 2012 Jan 1;72(1):220-9. doi: 10.1158/0008-5472.CAN-11-1976. Epub 2011 Nov 9.
• [4] ADAM22 and ADAM23 modulate the targeting of the Kv1 channel-associated protein LGI1 to the axon initial segment.J Cell Sci. 2019 Jan 16;132(2):jcs219774. doi: 10.1242/jcs.219774.
• [5] Dendritic Cells Expressing Triggering Receptor Expressed on Myeloid Cells-1 Correlate with Plaque Stability in Symptomatic and Asymptomatic Patients with Carotid Stenosis.PLoS One. 2016 May 5;11(5):e0154802. doi: 10.1371/journal.pone.0154802. eCollection 2016.
• [6] The LGI1-ADAM22 protein complex in synaptic transmission and synaptic disorders.Neurosci Res. 2017 Mar;116:39-45. doi: 10.1016/j.neures.2016.09.011. Epub 2016 Oct 4.
• [7] A Disintegrin and Metalloprotease-22 Attenuates Hypertrophic Remodeling in Mice Through Inhibition of the Protein Kinase B Signaling Pathway.J Am Heart Assoc. 2018 Jan 22;7(2):e005696. doi: 10.1161/JAHA.117.005696.
• [8] Leucine rich repeat LGI family member 3: Integrative analyses reveal its prognostic association with non-small cell lung cancer.Oncol Lett. 2019 Sep;18(3):3388-3398. doi: 10.3892/ol.2019.10648. Epub 2019 Jul 22.
• [9] Severe depletion of peripheral blood dendritic cell subsets in obstructive sleep apnea patients: A new link with cancer?.Cytokine. 2020 Jan;125:154831. doi: 10.1016/j.cyto.2019.154831. Epub 2019 Aug 29.
• [10] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [11] miR-449a Suppresses Tamoxifen Resistance in Human Breast Cancer Cells by Targeting ADAM22.Cell Physiol Biochem. 2018;50(1):136-149. doi: 10.1159/000493964. Epub 2018 Oct 2.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] 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.
• [14] 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.
• [15] Comparative effects of raloxifene, tamoxifen and estradiol on human osteoblasts in vitro: estrogen receptor dependent or independent pathways of raloxifene. J Steroid Biochem Mol Biol. 2009 Feb;113(3-5):281-9.
• [16] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [19] 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.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] 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.
• [22] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.