Details of Drug Off-Target (DOT)

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

• DOT Name: ADAMTS-like protein 4 (ADAMTSL4)
• Synonyms: ADAMTSL-4; Thrombospondin repeat-containing protein 1
• Gene Name: ADAMTSL4
• Related Disease:
  Acute lymphocytic leukaemia
  Childhood acute lymphoblastic leukemia
  Ectopia lentis 2, isolated, autosomal recessive
  Ectopia lentis et pupillae
  Marfan syndrome
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
  Isolated ectopia lentis
  Thrombotic thrombocytopenic purpura
  Coronary heart disease
  Geleophysic dysplasia
  Nasopharyngeal carcinoma
  Neoplasm
• UniProt ID: ATL4_HUMAN
• Pfam ID: PF19236 ; PF05986 ; PF08686 ; PF19030 ; PF00090
• Sequence:
  MENWTGRPWLYLLLLLSLPQLCLDQEVLSGHSLQTPTEEGQGPEGVWGPWVQWASCSQPC
  GVGVQRRSRTCQLPTVQLHPSLPLPPRPPRHPEALLPRGQGPRPQTSPETLPLYRTQSRG
  RGGPLRGPASHLGREETQEIRAARRSRLRDPIKPGMFGYGRVPFALPLHRNRRHPRSPPR
  SELSLISSRGEEAIPSPTPRAEPFSANGSPQTELPPTELSVHTPSPQAEPLSPETAQTEV
  APRTRPAPLRHHPRAQASGTEPPSPTHSLGEGGFFRASPQPRRPSSQGWASPQVAGRRPD
  PFPSVPRGRGQQGQGPWGTGGTPHGPRLEPDPQHPGAWLPLLSNGPHASSLWSLFAPSSP
  IPRCSGESEQLRACSQAPCPPEQPDPRALQCAAFNSQEFMGQLYQWEPFTEVQGSQRCEL
  NCRPRGFRFYVRHTEKVQDGTLCQPGAPDICVAGRCLSPGCDGILGSGRRPDGCGVCGGD
  DSTCRLVSGNLTDRGGPLGYQKILWIPAGALRLQIAQLRPSSNYLALRGPGGRSIINGNW
  AVDPPGSYRAGGTVFRYNRPPREEGKGESLSAEGPTTQPVDVYMIFQEENPGVFYQYVIS
  SPPPILENPTPEPPVPQLQPEILRVEPPLAPAPRPARTPGTLQRQVRIPQMPAPPHPRTP
  LGSPAAYWKRVGHSACSASCGKGVWRPIFLCISRESGEELDERSCAAGARPPASPEPCHG
  TPCPPYWEAGEWTSCSRSCGPGTQHRQLQCRQEFGGGGSSVPPERCGHLPRPNITQSCQL
  RLCGHWEVGSPWSQCSVRCGRGQRSRQVRCVGNNGDEVSEQECASGPPQPPSREACDMGP
  CTTAWFHSDWSSKCSAECGTGIQRRSVVCLGSGAALGPGQGEAGAGTGQSCPTGSRPPDM
  RACSLGPCERTWRWYTGPWGECSSECGSGTQRRDIICVSKLGTEFNVTSPSNCSHLPRPP
  ALQPCQGQACQDRWFSTPWSPCSRSCQGGTQTREVQCLSTNQTLSTRCPPQLRPSRKRPC
  NSQPCSQRPDDQCKDSSPHCPLVVQARLCVYPYYTATCCRSCAHVLERSPQDPS
• Function: Positive regulation of apoptosis. May facilitate FBN1 microfibril biogenesis.
• Tissue Specificity: Expressed in colon, heart, leukocyte, liver, lung, skeletal muscle, spleen, testis and placenta. Weaker expression in bone marrow, brain tissue, kidney and pancreas. Expression studies in fetal tissues reveal strong expression in heart, kidney, liver, lung and skeletal muscle, but weaker expression in fetal brain and skin.
• Reactome Pathway:
  O-glycosylation of TSR domain-containing proteins (R-HSA-5173214)
  Defective B3GALTL causes PpS (R-HSA-5083635)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[1]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[1]
Ectopia lentis 2, isolated, autosomal recessive	DIS3JPAJ	Strong	Autosomal recessive	[2]
Ectopia lentis et pupillae	DISJ4TF1	Strong	Autosomal recessive	[3]
Marfan syndrome	DISVEUWZ	Strong	Genetic Variation	[4]
Epithelial ovarian cancer	DIS56MH2	moderate	Biomarker	[5]
Ovarian cancer	DISZJHAP	moderate	Biomarker	[5]
Ovarian neoplasm	DISEAFTY	moderate	Biomarker	[5]
Isolated ectopia lentis	DISJWTN6	Supportive	Autosomal dominant	[6]
Thrombotic thrombocytopenic purpura	DIS3LDOU	Disputed	Biomarker	[7]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[8]
Geleophysic dysplasia	DISZOO1G	Limited	Biomarker	[9]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[10]
Neoplasm	DISZKGEW	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of ADAMTS-like protein 4 (ADAMTSL4).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of ADAMTS-like protein 4 (ADAMTSL4).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ADAMTS-like protein 4 (ADAMTSL4).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ADAMTS-like protein 4 (ADAMTSL4).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of ADAMTS-like protein 4 (ADAMTSL4).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of ADAMTS-like protein 4 (ADAMTSL4).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of ADAMTS-like protein 4 (ADAMTSL4).	[15]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of ADAMTS-like protein 4 (ADAMTSL4).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of ADAMTS-like protein 4 (ADAMTSL4).	[19]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of ADAMTS-like protein 4 (ADAMTSL4).	[20]

References

• [1] Differential gene expression patterns and interaction networks in BCR-ABL-positive and -negative adult acute lymphoblastic leukemias.J Clin Oncol. 2007 Apr 10;25(11):1341-9. doi: 10.1200/JCO.2006.09.3534. Epub 2007 Feb 20.
• [2] 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.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] ADAMTSL4 assessment in ectopia lentis reveals a recurrent founder mutation in Polynesians.Ophthalmic Genet. 2017 Dec;38(6):537-543. doi: 10.1080/13816810.2017.1309552. Epub 2017 Apr 10.
• [5] Cathepsin B and its interacting proteins, bikunin and TSRC1, correlate with TNF-induced apoptosis of ovarian cancer cells OV-90.FEBS Lett. 2006 Jan 9;580(1):245-50. doi: 10.1016/j.febslet.2005.12.005. Epub 2005 Dec 12.
• [6] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [7] The ADAMTS(L) family and human genetic disorders.Hum Mol Genet. 2011 Oct 15;20(R2):R163-7. doi: 10.1093/hmg/ddr361. Epub 2011 Aug 31.
• [8] Whole-exome sequencing in individuals with multiple cardiovascular risk factors and normal coronary arteries.Coron Artery Dis. 2016 Jun;27(4):257-66. doi: 10.1097/MCA.0000000000000357.
• [9] Genetic and functional linkage between ADAMTS superfamily proteins and fibrillin-1: a novel mechanism influencing microfibril assembly and function.Cell Mol Life Sci. 2011 Oct;68(19):3137-48. doi: 10.1007/s00018-011-0780-9. Epub 2011 Aug 20.
• [10] Correlation of five secretory proteins with the nasopharyngeal carcinoma metastasis and the clinical applications.Oncotarget. 2017 Apr 25;8(17):29383-29394. doi: 10.18632/oncotarget.14725.
• [11] 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.
• [12] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Locus-Specific Differential DNA Methylation and Urinary Arsenic: An Epigenome-Wide Association Study in Blood among Adults with Low-to-Moderate Arsenic Exposure. Environ Health Perspect. 2020 Jun;128(6):67015. doi: 10.1289/EHP6263. Epub 2020 Jun 30.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.