Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT70Z4II)

• DOT Name: Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9)
• Synonyms: ADAM 9; EC 3.4.24.-; Cellular disintegrin-related protein; Meltrin-gamma; Metalloprotease/disintegrin/cysteine-rich protein 9; Myeloma cell metalloproteinase
• Gene Name: ADAM9
• Related Disease:
  ADAM9-related retinopathy
  Cone-rod dystrophy 9
  Cone-rod dystrophy
• UniProt ID: ADAM9_HUMAN
• EC Number: 3.4.24.-
• Pfam ID: PF08516 ; PF00200 ; PF01562 ; PF01421
• Sequence:
  MGSGARFPSGTLRVRWLLLLGLVGPVLGAARPGFQQTSHLSSYEIITPWRLTRERREAPR
  PYSKQVSYVIQAEGKEHIIHLERNKDLLPEDFVVYTYNKEGTLITDHPNIQNHCHYRGYV
  EGVHNSSIALSDCFGLRGLLHLENASYGIEPLQNSSHFEHIIYRMDDVYKEPLKCGVSNK
  DIEKETAKDEEEEPPSMTQLLRRRRAVLPQTRYVELFIVVDKERYDMMGRNQTAVREEMI
  LLANYLDSMYIMLNIRIVLVGLEIWTNGNLINIVGGAGDVLGNFVQWREKFLITRRRHDS
  AQLVLKKGFGGTAGMAFVGTVCSRSHAGGINVFGQITVETFASIVAHELGHNLGMNHDDG
  RDCSCGAKSCIMNSGASGSRNFSSCSAEDFEKLTLNKGGNCLLNIPKPDEAYSAPSCGNK
  LVDAGEECDCGTPKECELDPCCEGSTCKLKSFAECAYGDCCKDCRFLPGGTLCRGKTSEC
  DVPEYCNGSSQFCQPDVFIQNGYPCQNNKAYCYNGMCQYYDAQCQVIFGSKAKAAPKDCF
  IEVNSKGDRFGNCGFSGNEYKKCATGNALCGKLQCENVQEIPVFGIVPAIIQTPSRGTKC
  WGVDFQLGSDVPDPGMVNEGTKCGAGKICRNFQCVDASVLNYDCDVQKKCHGHGVCNSNK
  NCHCENGWAPPNCETKGYGGSVDSGPTYNEMNTALRDGLLVFFFLIVPLIVCAIFIFIKR
  DQLWRSYFRKKRSQTYESDGKNQANPSRQPGSVPRHVSPVTPPREVPIYANRFAVPTYAA
  KQPQQFPSRPPPPQPKVSSQGNLIPARPAPAPPLYSSLT
• Function: Metalloprotease that cleaves and releases a number of molecules with important roles in tumorigenesis and angiogenesis, such as TEK, KDR, EPHB4, CD40, VCAM1 and CDH5. May mediate cell-cell, cell-matrix interactions and regulate the motility of cells via interactions with integrins; [Isoform 2]: May act as alpha-secretase for amyloid precursor protein (APP).
• Tissue Specificity: Widely expressed. Expressed in chondrocytes. Isoform 2 is highly expressed in liver and heart.
• KEGG Pathway: Efferocytosis (hsa04148)
• Reactome Pathway: Collagen degradation (R-HSA-1442490)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
ADAM9-related retinopathy	DIS3FXZL	Definitive	Autosomal recessive	[1]
Cone-rod dystrophy 9	DISW6J8X	Definitive	Autosomal recessive	[2]
Cone-rod dystrophy	DISY9RWN	Supportive	Autosomal dominant	[3]

18 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 9 (ADAM9).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9).	[12]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9).	[13]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9).	[14]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9).	[16]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9).	[17]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9).	[21]
Phorbol 12,13-butyrate	DMZWTY7	Investigative	Phorbol 12,13-butyrate increases the expression of Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9).	[15]

References

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• [2] Pelvic aneurysmal bone cyst in a dog. J Vet Med Sci. 1997 Nov;59(11):1027-30. doi: 10.1292/jvms.59.1027.
• [3] Loss of the metalloprotease ADAM9 leads to cone-rod dystrophy in humans and retinal degeneration in mice. Am J Hum Genet. 2009 May;84(5):683-91. doi: 10.1016/j.ajhg.2009.04.005. Epub 2009 Apr 30.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Regulation of secretases by all-trans-retinoic acid. FEBS J. 2009 May;276(9):2645-55. doi: 10.1111/j.1742-4658.2009.06992.x. Epub 2009 Mar 25.
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• [8] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Oxidative stress induces ADAM9 protein expression in human prostate cancer cells. Cancer Res. 2006 Oct 1;66(19):9519-26. doi: 10.1158/0008-5472.CAN-05-4375.
• [11] 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.
• [12] 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.
• [13] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [14] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] Cannabidiol Modulates the Expression of Alzheimer's Disease-Related Genes in Mesenchymal Stem Cells. Int J Mol Sci. 2016 Dec 23;18(1):26. doi: 10.3390/ijms18010026.
• [17] 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.
• [18] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [19] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [20] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.