Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ1TO02)

• DOT Name: Cadherin-15 (CDH15)
• Synonyms: Cadherin-14; Muscle cadherin; M-cadherin
• Gene Name: CDH15
• Related Disease:
  Medium chain acyl-CoA dehydrogenase deficiency
  Alcohol dependence
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Clear cell renal carcinoma
  Congenital diaphragmatic hernia
  Congestive heart failure
  Endometriosis
  Polycystic ovarian syndrome
  Renal cell carcinoma
  Autism
  Hepatocellular carcinoma
  Hypoglycemia
  Rhabdomyosarcoma
  Schizophrenia
  Autosomal dominant non-syndromic intellectual disability
  Intellectual disability
  Bone osteosarcoma
  Colorectal carcinoma
  Intellectual disability, autosomal dominant 3
  Matthew-Wood syndrome
  Neoplasm
  Osteosarcoma
  Pancreatic ductal carcinoma
• UniProt ID: CAD15_HUMAN
• Pfam ID: PF01049 ; PF00028
• Sequence:
  MDAAFLLVLGLLAQSLCLSLGVPGWRRPTTLYPWRRAPALSRVRRAWVIPPISVSENHKR
  LPYPLVQIKSDKQQLGSVIYSIQGPGVDEEPRGVFSIDKFTGKVFLNAMLDREKTDRFRL
  RAFALDLGGSTLEDPTDLEIVVVDQNDNRPAFLQEAFTGRVLEGAVPGTYVTRAEATDAD
  DPETDNAALRFSILQQGSPELFSIDELTGEIRTVQVGLDREVVAVYNLTLQVADMSGDGL
  TATASAIITLDDINDNAPEFTRDEFFMEAIEAVSGVDVGRLEVEDRDLPGSPNWVARFTI
  LEGDPDGQFTIRTDPKTNEGVLSIVKALDYESCEHYELKVSVQNEAPLQAAALRAERGQA
  KVRVHVQDTNEPPVFQENPLRTSLAEGAPPGTLVATFSARDPDTEQLQRLSYSKDYDPED
  WLQVDAATGRIQTQHVLSPASPFLKGGWYRAIVLAQDDASQPRTATGTLSIEILEVNDHA
  PVLAPPPPGSLCSEPHQGPGLLLGATDEDLPPHGAPFHFQLSPRLPELGRNWSLSQVNVS
  HARLRPRHQVPEGLHRLSLLLRDSGQPPQQREQPLNVTVCRCGKDGVCLPGAAALLAGGT
  GLSLGALVIVLASALLLLVLVLLVALRARFWKQSRGKGLLHGPQDDLRDNVLNYDEQGGG
  EEDQDAYDISQLRHPTALSLPLGPPPLRRDAPQGRLHPQPPRVLPTSPLDIADFINDGLE
  AADSDPSVPPYDTALIYDYEGDGSVAGTLSSILSSQGDEDQDYDYLRDWGPRFARLADMY
  GHPCGLEYGARWDHQAREGLSPGALLPRHRGRTA
• Function: Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. M-cadherin is part of the myogenic program and may provide a trigger for terminal muscle differentiation.
• Tissue Specificity: Expressed in the brain and cerebellum.
• KEGG Pathway: Cell adhesion molecules (hsa04514)
• Reactome Pathway:
  Myogenesis (R-HSA-525793)
  Adherens junctions interactions (R-HSA-418990)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Medium chain acyl-CoA dehydrogenase deficiency	DISB8C4K	Definitive	Genetic Variation	[1]
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[3]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Cardiac failure	DISDC067	Strong	Altered Expression	[4]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[5]
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Biomarker	[6]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[4]
Endometriosis	DISX1AG8	Strong	Genetic Variation	[7]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[8]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[5]
Autism	DISV4V1Z	moderate	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	moderate	Posttranslational Modification	[9]
Hypoglycemia	DISRCKR7	moderate	Genetic Variation	[10]
Rhabdomyosarcoma	DISNR7MS	moderate	Genetic Variation	[11]
Schizophrenia	DISSRV2N	moderate	Biomarker	[2]
Autosomal dominant non-syndromic intellectual disability	DISD6L06	Supportive	Autosomal dominant	[12]
Intellectual disability	DISMBNXP	Disputed	Autosomal dominant	[13]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[14]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[15]
Intellectual disability, autosomal dominant 3	DISAA7AX	Limited	Autosomal dominant	[16]
Matthew-Wood syndrome	DISA7HR7	Limited	Biomarker	[17]
Neoplasm	DISZKGEW	Limited	Biomarker	[18]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[14]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[17]

1 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 Cadherin-15 (CDH15).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cadherin-15 (CDH15).	[20]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Cadherin-15 (CDH15).	[21]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cadherin-15 (CDH15).	[22]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Cadherin-15 (CDH15).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Cadherin-15 (CDH15).	[24]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Cadherin-15 (CDH15).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cadherin-15 (CDH15).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Cadherin-15 (CDH15).	[27]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Cadherin-15 (CDH15).	[28]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the expression of Cadherin-15 (CDH15).	[29]

References

• [1] Sudden death in medium chain acyl-coenzyme a dehydrogenase deficiency (MCADD) despite newborn screening.Mol Genet Metab. 2010 Sep;101(1):33-9. doi: 10.1016/j.ymgme.2010.05.007. Epub 2010 Jun 9.
• [2] Cadherins and neuropsychiatric disorders.Brain Res. 2012 Aug 27;1470:130-44. doi: 10.1016/j.brainres.2012.06.020. Epub 2012 Jul 2.
• [3] Lost in translation? A systematic database of gene expression in breast cancer.Pathobiology. 2008;75(2):112-8. doi: 10.1159/000123849. Epub 2008 Jun 10.
• [4] The energy substrate switch during development of heart failure: gene regulatory mechanisms (Review).Int J Mol Med. 1998 Jan;1(1):17-24. doi: 10.3892/ijmm.1.1.17.
• [5] MicroRNA-720 Regulates E-cadherin-E-catenin Complex and Promotes Renal Cell Carcinoma.Mol Cancer Ther. 2017 Dec;16(12):2840-2848. doi: 10.1158/1535-7163.MCT-17-0400. Epub 2017 Aug 11.
• [6] Ventricular Performance is Associated with Need for Extracorporeal Membrane Oxygenation in Newborns with Congenital Diaphragmatic Hernia.J Pediatr. 2017 Dec;191:28-34.e1. doi: 10.1016/j.jpeds.2017.08.060. Epub 2017 Oct 13.
• [7] Association of three single nucleotide polymorphisms of the E-cadherin gene with endometriosis in a Chinese population.Reproduction. 2007 Aug;134(2):373-8. doi: 10.1530/REP-07-0104.
• [8] Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
• [9] Meta-analysis of possible role of cadherin gene methylation in evolution and prognosis of hepatocellular carcinoma with a PRISMA guideline.Medicine (Baltimore). 2017 Apr;96(16):e6650. doi: 10.1097/MD.0000000000006650.
• [10] Risk stratification by residual enzyme activity after newborn screening for medium-chain acyl-CoA dehyrogenase deficiency: data from a cohort study.Orphanet J Rare Dis. 2012 May 25;7:30. doi: 10.1186/1750-1172-7-30.
• [11] Zebrafish rhabdomyosarcoma reflects the developmental stage of oncogene expression during myogenesis.Development. 2013 Jul;140(14):3040-50. doi: 10.1242/dev.087858.
• [12] Alterations in CDH15 and KIRREL3 in patients with mild to severe intellectual disability. Am J Hum Genet. 2008 Dec;83(6):703-13. doi: 10.1016/j.ajhg.2008.10.020. Epub 2008 Nov 13.
• [13] 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.
• [14] The cyclin-dependent kinase inhibitor flavopiridol (alvocidib) inhibits metastasis of human osteosarcoma cells.Oncotarget. 2018 May 4;9(34):23505-23518. doi: 10.18632/oncotarget.25239. eCollection 2018 May 4.
• [15] Identification of a novel tumor-associated antigen, cadherin 3/P-cadherin, as a possible target for immunotherapy of pancreatic, gastric, and colorectal cancers.Clin Cancer Res. 2008 Oct 15;14(20):6487-95. doi: 10.1158/1078-0432.CCR-08-1086.
• [16] 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.
• [17] Cadherin-1 and cadherin-3 cooperation determines the aggressiveness of pancreatic ductal adenocarcinoma.Br J Cancer. 2018 Feb 20;118(4):546-557. doi: 10.1038/bjc.2017.411. Epub 2017 Nov 21.
• [18] High expression of CDH3 predicts a good prognosis for colon adenocarcinoma patients.Exp Ther Med. 2019 Jul;18(1):841-847. doi: 10.3892/etm.2019.7638. Epub 2019 Jun 3.
• [19] 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.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [24] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [25] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [26] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [27] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [28] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [29] Roles of acyl-CoA synthetase long-chain family member 5 and colony stimulating factor 2 in inhibition of palmitic or stearic acids in lung cancer cell proliferation and metabolism. Cell Biol Toxicol. 2021 Feb;37(1):15-34. doi: 10.1007/s10565-020-09520-w. Epub 2020 Apr 28.