Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV3Q0DS)

• DOT Name: A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9)
• Synonyms: ADAM-TS 9; ADAM-TS9; ADAMTS-9; EC 3.4.24.-
• Gene Name: ADAMTS9
• Related Disease:
  Rheumatoid arthritis
  Carcinoma
  Cleft palate
  Colorectal carcinoma
  Corneal neovascularization
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Gastric cancer
  Gastric neoplasm
  Hydrocephalus
  Isolated cleft palate
  Knee osteoarthritis
  Malignant tumor of nasopharynx
  Nasopharyngeal carcinoma
  Neoplasm
  Nephronophthisis
  Non-alcoholic fatty liver disease
  Non-insulin dependent diabetes
  Osteoarthritis
  Peters plus syndrome
  Primary hyperparathyroidism
  Prostate neoplasm
  Psoriatic arthritis
  Smith-McCort dysplasia 1
  Stomach cancer
  Polycystic ovarian syndrome
  Type-1/2 diabetes
  Nephronophthisis 1
  Breast cancer
  Breast carcinoma
  Acute myelogenous leukaemia
  Asthma
  Carcinoma of esophagus
  Ciliopathy
  Clear cell renal carcinoma
  Neoplasm of esophagus
  Plasma cell myeloma
• UniProt ID: ATS9_HUMAN
• EC Number: 3.4.24.-
• Pfam ID: PF17771 ; PF19236 ; PF05986 ; PF08685 ; PF01562 ; PF01421 ; PF19030 ; PF00090
• Sequence:
  MQFVSWATLLTLLVRDLAEMGSPDAAAAVRKDRLHPRQVKLLETLSEYEIVSPIRVNALG
  EPFPTNVHFKRTRRSINSATDPWPAFASSSSSSTSSQAHYRLSAFGQQFLFNLTANAGFI
  APLFTVTLLGTPGVNQTKFYSEEEAELKHCFYKGYVNTNSEHTAVISLCSGMLGTFRSHD
  GDYFIEPLQSMDEQEDEEEQNKPHIIYRRSAPQREPSTGRHACDTSEHKNRHSKDKKKTR
  ARKWGERINLAGDVAALNSGLATEAFSAYGNKTDNTREKRTHRRTKRFLSYPRFVEVLVV
  ADNRMVSYHGENLQHYILTLMSIVASIYKDPSIGNLINIVIVNLIVIHNEQDGPSISFNA
  QTTLKNFCQWQHSKNSPGGIHHDTAVLLTRQDICRAHDKCDTLGLAELGTICDPYRSCSI
  SEDSGLSTAFTIAHELGHVFNMPHDDNNKCKEEGVKSPQHVMAPTLNFYTNPWMWSKCSR
  KYITEFLDTGYGECLLNEPESRPYPLPVQLPGILYNVNKQCELIFGPGSQVCPYMMQCRR
  LWCNNVNGVHKGCRTQHTPWADGTECEPGKHCKYGFCVPKEMDVPVTDGSWGSWSPFGTC
  SRTCGGGIKTAIRECNRPEPKNGGKYCVGRRMKFKSCNTEPCLKQKRDFRDEQCAHFDGK
  HFNINGLLPNVRWVPKYSGILMKDRCKLFCRVAGNTAYYQLRDRVIDGTPCGQDTNDICV
  QGLCRQAGCDHVLNSKARRDKCGVCGGDNSSCKTVAGTFNTVHYGYNTVVRIPAGATNID
  VRQHSFSGETDDDNYLALSSSKGEFLLNGNFVVTMAKREIRIGNAVVEYSGSETAVERIN
  STDRIEQELLLQVLSVGKLYNPDVRYSFNIPIEDKPQQFYWNSHGPWQACSKPCQGERKR
  KLVCTRESDQLTVSDQRCDRLPQPGHITEPCGTDCDLRWHVASRSECSAQCGLGYRTLDI
  YCAKYSRLDGKTEKVDDGFCSSHPKPSNREKCSGECNTGGWRYSAWTECSKSCDGGTQRR
  RAICVNTRNDVLDDSKCTHQEKVTIQRCSEFPCPQWKSGDWSECLVTCGKGHKHRQVWCQ
  FGEDRLNDRMCDPETKPTSMQTCQQPECASWQAGPWGQCSVTCGQGYQLRAVKCIIGTYM
  SVVDDNDCNAATRPTDTQDCELPSCHPPPAAPETRRSTYSAPRTQWRFGSWTPCSATCGK
  GTRMRYVSCRDENGSVADESACATLPRPVAKEECSVTPCGQWKALDWSSCSVTCGQGRAT
  RQVMCVNYSDHVIDRSECDQDYIPETDQDCSMSPCPQRTPDSGLAQHPFQNEDYRPRSAS
  PSRTHVLGGNQWRTGPWGACSSTCAGGSQRRVVVCQDENGYTANDCVERIKPDEQRACES
  GPCPQWAYGNWGECTKLCGGGIRTRLVVCQRSNGERFPDLSCEILDKPPDREQCNTHACP
  HDAAWSTGPWSSCSVSCGRGHKQRNVYCMAKDGSHLESDYCKHLAKPHGHRKCRGGRCPK
  WKAGAWSQCSVSCGRGVQQRHVGCQIGTHKIARETECNPYTRPESERDCQGPRCPLYTWR
  AEEWQECTKTCGEGSRYRKVVCVDDNKNEVHGARCDVSKRPVDRESCSLQPCEYVWITGE
  WSECSVTCGKGYKQRLVSCSEIYTGKENYEYSYQTTINCPGTQPPSVHPCYLRDCPVSAT
  WRVGNWGSCSVSCGVGVMQRSVQCLTNEDQPSHLCHTDLKPEERKTCRNVYNCELPQNCK
  EVKRLKGASEDGEYFLMIRGKLLKIFCAGMHSDHPKEYVTLVHGDSENFSEVYGHRLHNP
  TECPYNGSRRDDCQCRKDYTAAGFSSFQKIRIDLTSMQIITTDLQFARTSEGHPVPFATA
  GDCYSAAKCPQGRFSINLYGTGLSLTESARWISQGNYAVSDIKKSPDGTRVVGKCGGYCG
  KCTPSSGTGLEVRVL
• Function: Cleaves the large aggregating proteoglycans, aggrecan (at the '1838-Glu-|-Ala-1839' site) and versican (at the '1428-Glu-|-Ala-1429' site). Has a protease-independent function in promoting the transport from the endoplasmic reticulum to the Golgi apparatus of a variety of secretory cargos.
• Tissue Specificity: Highly expressed in all fetal tissues. Expressed in a number of adult tissues with highest expression in heart, placenta and skeletal muscle.
• Reactome Pathway:
  Defective B3GALTL causes PpS (R-HSA-5083635)
  O-glycosylation of TSR domain-containing proteins (R-HSA-5173214)
  Degradation of the extracellular matrix (R-HSA-1474228)

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Rheumatoid arthritis	DISTSB4J	Definitive	Altered Expression	[1]
Carcinoma	DISH9F1N	Strong	Posttranslational Modification	[2]
Cleft palate	DIS6G5TF	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Corneal neovascularization	DISKOGZP	Strong	Biomarker	[5]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[6]
Gastric cancer	DISXGOUK	Strong	Biomarker	[7]
Gastric neoplasm	DISOKN4Y	Strong	Posttranslational Modification	[7]
Hydrocephalus	DISIZUF7	Strong	Biomarker	[8]
Isolated cleft palate	DISV80CD	Strong	Biomarker	[3]
Knee osteoarthritis	DISLSNBJ	Strong	Genetic Variation	[9]
Malignant tumor of nasopharynx	DISTGIGF	Strong	Biomarker	[5]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Nephronophthisis	DISXU4HY	Strong	Genetic Variation	[8]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[10]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[11]
Osteoarthritis	DIS05URM	Strong	Biomarker	[12]
Peters plus syndrome	DISIUM7O	Strong	Biomarker	[3]
Primary hyperparathyroidism	DISB4U1Q	Strong	Biomarker	[13]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[14]
Psoriatic arthritis	DISLWTG2	Strong	Genetic Variation	[15]
Smith-McCort dysplasia 1	DIS8072R	Strong	Biomarker	[16]
Stomach cancer	DISKIJSX	Strong	Biomarker	[7]
Polycystic ovarian syndrome	DISZ2BNG	moderate	Altered Expression	[17]
Type-1/2 diabetes	DISIUHAP	moderate	Genetic Variation	[18]
Nephronophthisis 1	DIS7QNQ3	Supportive	Autosomal recessive	[8]
Breast cancer	DIS7DPX1	Disputed	Posttranslational Modification	[2]
Breast carcinoma	DIS2UE88	Disputed	Posttranslational Modification	[2]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[19]
Asthma	DISW9QNS	Limited	Genetic Variation	[20]
Carcinoma of esophagus	DISS6G4D	Limited	Altered Expression	[21]
Ciliopathy	DIS10G4I	Limited	Autosomal recessive	[22]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[23]
Neoplasm of esophagus	DISOLKAQ	Limited	Altered Expression	[21]
Plasma cell myeloma	DIS0DFZ0	Limited	Biomarker	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9).	[25]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9).	[26]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9).	[27]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9).	[28]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9).	[29]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9).	[30]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9).	[31]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9).	[32]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9).	[33]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9).	[34]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9).	[35]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9).	[36]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9).	[37]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9).	[38]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9).	[40]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9).	[36]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9).	[42]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9).	[43]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9).	[36]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9).	[44]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Glucosamine	DM4ZLFD	Approved	Glucosamine decreases the cleavage of A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9).	[41]

References

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• [3] ADAMTS9 and ADAMTS20 are differentially affected by loss of B3GLCT in mouse model of Peters plus syndrome.Hum Mol Genet. 2019 Dec 15;28(24):4053-4066. doi: 10.1093/hmg/ddz225.
• [4] ADAMTS9 is Silenced by Epigenetic Disruption in Colorectal Cancer and Inhibits Cell Growth and Metastasis by Regulating Akt/p53 Signaling.Cell Physiol Biochem. 2017;44(4):1370-1380. doi: 10.1159/000485534. Epub 2017 Nov 30.
• [5] ADAMTS9 is a cell-autonomously acting, anti-angiogenic metalloprotease expressed by microvascular endothelial cells.Am J Pathol. 2010 Mar;176(3):1494-504. doi: 10.2353/ajpath.2010.090655. Epub 2010 Jan 21.
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• [8] Mutations of ADAMTS9 Cause Nephronophthisis-Related Ciliopathy. Am J Hum Genet. 2019 Jan 3;104(1):45-54. doi: 10.1016/j.ajhg.2018.11.003.
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• [10] MicroRNA-190b regulates lipid metabolism and insulin sensitivity by targeting IGF-1 and ADAMTS9 in non-alcoholic fatty liver disease.J Cell Biochem. 2018 Jul;119(7):5864-5874. doi: 10.1002/jcb.26776. Epub 2018 Mar 25.
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