Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRMFI04)

• DOT Name: A disintegrin and metalloproteinase with thrombospondin motifs 18 (ADAMTS18)
• Synonyms: ADAM-TS 18; ADAM-TS18; ADAMTS-18; EC 3.4.24.-
• Gene Name: ADAMTS18
• Related Disease:
  Cone-rod dystrophy
  Cone-rod dystrophy 2
  Microcornea-myopic chorioretinal atrophy
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cerebral infarction
  Cervical cancer
  Cervical carcinoma
  Clear cell renal carcinoma
  Colitis
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Dilated cardiomyopathy 1A
  Disorder of orbital region
  Hematologic disease
  High blood pressure
  Knobloch syndrome
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Melanoma
  Metabolic disorder
  Myopia
  Retinopathy
  Trichohepatoenteric syndrome
  Gastric cancer
  Nasopharyngeal carcinoma
  Carcinoma
  Inherited retinal dystrophy
• UniProt ID: ATS18_HUMAN
• EC Number: 3.4.24.-
• Pfam ID: PF17771 ; PF19236 ; PF05986 ; PF01562 ; PF08686 ; PF01421 ; PF19030 ; PF00090
• Sequence:
  MECALLLACAFPAAGSGPPRGLAGLGRVAKALQLCCLCCASVAAALASDSSSGASGLNDD
  YVFVTPVEVDSAGSYISHDILHNGRKKRSAQNARSSLHYRFSAFGQELHLELKPSAILSS
  HFIVQVLGKDGASETQKPEVQQCFYQGFIRNDSSSSVAVSTCAGLSGLIRTRKNEFLISP
  LPQLLAQEHNYSSPAGHHPHVLYKRTAEEKIQRYRGYPGSGRNYPGYSPSHIPHASQSRE
  TEYHHRRLQKQHFCGRRKKYAPKPPTEDTYLRFDEYGSSGRPRRSAGKSQKGLNVETLVV
  ADKKMVEKHGKGNVTTYILTVMNMVSGLFKDGTIGSDINVVVVSLILLEQEPGGLLINHH
  ADQSLNSFCQWQSALIGKNGKRHDHAILLTGFDICSWKNEPCDTLGFAPISGMCSKYRSC
  TINEDTGLGLAFTIAHESGHNFGMIHDGEGNPCRKAEGNIMSPTLTGNNGVFSWSSCSRQ
  YLKKFLSTPQAGCLVDEPKQAGQYKYPDKLPGQIYDADTQCKWQFGAKAKLCSLGFVKDI
  CKSLWCHRVGHRCETKFMPAAEGTVCGLSMWCRQGQCVKFGELGPRPIHGQWSAWSKWSE
  CSRTCGGGVKFQERHCNNPKPQYGGLFCPGSSRIYQLCNINPCNENSLDFRAQQCAEYNS
  KPFRGWFYQWKPYTKVEEEDRCKLYCKAENFEFFFAMSGKVKDGTPCSPNKNDVCIDGVC
  ELVGCDHELGSKAVSDACGVCKGDNSTCKFYKGLYLNQHKANEYYPVVLIPAGARSIEIQ
  ELQVSSSYLAVRSLSQKYYLTGGWSIDWPGEFPFAGTTFEYQRSFNRPERLYAPGPTNET
  LVFEILMQGKNPGIAWKYALPKVMNGTPPATKRPAYTWSIVQSECSVSCGGGYINVKAIC
  LRDQNTQVNSSFCSAKTKPVTEPKICNAFSCPAYWMPGEWSTCSKACAGGQQSRKIQCVQ
  KKPFQKEEAVLHSLCPVSTPTQVQACNSHACPPQWSLGPWSQCSKTCGRGVRKRELLCKG
  SAAETLPESQCTSLPRPELQEGCVLGRCPKNSRLQWVASSWSECSATCGLGVRKREMKCS
  EKGFQGKLITFPERRCRNIKKPNLDLEETCNRRACPAHPVYNMVAGWYSLPWQQCTVTCG
  GGVQTRSVHCVQQGRPSSSCLLHQKPPVLRACNTNFCPAPEKREDPSCVDFFNWCHLVPQ
  HGVCNHKFYGKQCCKSCTRKI
• Tissue Specificity: Expressed in fetal lung, liver, and kidney and in adult brain, prostate, submaxillary gland, and endothelium.
• 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

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cone-rod dystrophy	DISY9RWN	Definitive	Biomarker	[1]
Cone-rod dystrophy 2	DISX2RWY	Definitive	Biomarker	[1]
Microcornea-myopic chorioretinal atrophy	DIS4CYCX	Definitive	Autosomal recessive	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[5]
Cerebral infarction	DISR1WNP	Strong	Biomarker	[6]
Cervical cancer	DISFSHPF	Strong	Biomarker	[7]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[7]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[8]
Colitis	DISAF7DD	Strong	Biomarker	[9]
Colon cancer	DISVC52G	Strong	Biomarker	[9]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[9]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[10]
Disorder of orbital region	DISH0ECJ	Strong	Genetic Variation	[11]
Hematologic disease	DIS9XD9A	Strong	Biomarker	[12]
High blood pressure	DISY2OHH	Strong	Biomarker	[4]
Knobloch syndrome	DIS20FJI	Strong	Genetic Variation	[13]
Lung cancer	DISCM4YA	Strong	Biomarker	[14]
Lung carcinoma	DISTR26C	Strong	Biomarker	[14]
Lung neoplasm	DISVARNB	Strong	Biomarker	[14]
Melanoma	DIS1RRCY	Strong	Genetic Variation	[15]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[4]
Myopia	DISK5S60	Strong	Genetic Variation	[16]
Retinopathy	DISB4B0F	Strong	Genetic Variation	[11]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[16]
Gastric cancer	DISXGOUK	moderate	Posttranslational Modification	[17]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Biomarker	[17]
Carcinoma	DISH9F1N	Limited	Biomarker	[5]
Inherited retinal dystrophy	DISGGL77	Limited	Autosomal recessive	[11]

4 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 18 (ADAMTS18).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 18 (ADAMTS18).	[19]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 18 (ADAMTS18).	[20]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 18 (ADAMTS18).	[21]

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 affects the methylation of A disintegrin and metalloproteinase with thrombospondin motifs 18 (ADAMTS18).	[22]

References

• [1] Expansion of ocular phenotypic features associated with mutations in ADAMTS18.JAMA Ophthalmol. 2014 Aug;132(8):996-1001. doi: 10.1001/jamaophthalmol.2014.940.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] The development of monoclonal anti-ADAMTS18 antibodies with precise validation of ADAMTS18 post-translational modification status in living organisms.Biochem Biophys Res Commun. 2017 Oct 21;492(3):404-411. doi: 10.1016/j.bbrc.2017.08.086. Epub 2017 Aug 24.
• [4] A Disintegrin and Metalloproteinase with Thrombospondin Motifs 18 Deficiency Leads to Visceral Adiposity and Associated Metabolic Syndrome in Mice.Am J Pathol. 2018 Feb;188(2):461-473. doi: 10.1016/j.ajpath.2017.10.020. Epub 2017 Nov 21.
• [5] Epigenetic silencing of ADAMTS18 promotes cell migration and invasion of breast cancer through AKT and NF-B signaling.Cancer Med. 2017 Jun;6(6):1399-1408. doi: 10.1002/cam4.1076. Epub 2017 May 15.
• [6] Adamts18 deficiency increases arterial thrombus formation associated with vascular defects in mice.Biochem Biophys Res Commun. 2018 Feb 19;496(4):1362-1368. doi: 10.1016/j.bbrc.2018.02.032. Epub 2018 Feb 6.
• [7] Downregulation of ADAMTS18 May Serve as a Poor Prognostic Biomarker for Cervical Cancer Patients.Appl Immunohistochem Mol Morphol. 2018 Oct;26(9):670-675. doi: 10.1097/PAI.0000000000000496.
• [8] Hypermethylation of the 16q23.1 tumor suppressor gene ADAMTS18 in clear cell renal cell carcinoma.Int J Mol Sci. 2015 Jan 5;16(1):1051-65. doi: 10.3390/ijms16011051.
• [9] Adamts18 deficiency promotes colon carcinogenesis by enhancing -catenin and p38MAPK/ERK1/2 signaling in the mouse model of AOM/DSS-induced colitis-associated colorectal cancer.Oncotarget. 2017 Mar 21;8(12):18979-18990. doi: 10.18632/oncotarget.14866.
• [10] Relationship Between ADAMTS8, ADAMTS18, and ADAMTS20 (A Disintegrin and Metalloproteinase with Thrombospondin Motifs) Expressions and Tumor Molecular Classification, Clinical Pathological Parameters, and Prognosis in Breast Invasive Ductal Carcinoma.Med Sci Monit. 2018 Jun 3;24:3726-3735. doi: 10.12659/MSM.907310.
• [11] The ADAMTS18 gene is responsible for autosomal recessive early onset severe retinal dystrophy. Orphanet J Rare Dis. 2013 Jan 28;8:16. doi: 10.1186/1750-1172-8-16.
• [12] ADAMTS-18: a metalloproteinase with multiple functions.Front Biosci (Landmark Ed). 2014 Jun 1;19(8):1456-67. doi: 10.2741/4296.
• [13] Identification of ADAMTS18 as a gene mutated in Knobloch syndrome. J Med Genet. 2011 Sep;48(9):597-601. doi: 10.1136/jmedgenet-2011-100306.
• [14] Inactivation of ADAMTS18 by aberrant promoter hypermethylation contribute to lung cancer progression.J Cell Physiol. 2019 May;234(5):6965-6975. doi: 10.1002/jcp.27439. Epub 2018 Nov 11.
• [15] Mutational and functional analysis reveals ADAMTS18 metalloproteinase as a novel driver in melanoma.Mol Cancer Res. 2010 Nov;8(11):1513-25. doi: 10.1158/1541-7786.MCR-10-0262. Epub 2010 Oct 13.
• [16] The syndrome of microcornea, myopic chorioretinal atrophy, and telecanthus (MMCAT) is caused by mutations in ADAMTS18. Hum Mutat. 2013 Sep;34(9):1195-9. doi: 10.1002/humu.22374. Epub 2013 Jul 19.
• [17] High-resolution melting analysis of ADAMTS18 methylation levels in gastric, colorectal and pancreatic cancers.Med Oncol. 2010 Sep;27(3):998-1004. doi: 10.1007/s12032-009-9323-8. Epub 2009 Oct 6.
• [18] 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.
• [19] 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.
• [20] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [21] Adipogenic Effects and Gene Expression Profiling of Firemaster? 550 Components in Human Primary Preadipocytes. Environ Health Perspect. 2017 Sep 14;125(9):097013. doi: 10.1289/EHP1318.
• [22] 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.