Details of Drug Off-Target (DOT)

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

• DOT Name: Cadherin-related family member 5 (CDHR5)
• Synonyms: Mu-protocadherin; Mucin and cadherin-like protein; Mucin-like protocadherin; MLPCDH
• Gene Name: CDHR5
• Related Disease:
  Autosomal dominant polycystic kidney disease
  Cholelithiasis
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Gerstmann-Straussler-Scheinker syndrome
  Hepatocellular carcinoma
  Hereditary nonpolyposis colon cancer
  Neoplasm
  Renal cell carcinoma
  Systemic sclerosis
  Systemic lupus erythematosus
• UniProt ID: CDHR5_HUMAN
• PDB ID: 6OAE
• Sequence:
  MGSWALLWPPLLFTGLLVRPPGTMAQAQYCSVNKDIFEVEENTNVTEPLVDIHVPEGQEV
  TLGALSTPFAFRIQGNQLFLNVTPDYEEKSLLEAQLLCQSGGTLVTQLRVFVSVLDVNDN
  APEFPFKTKEIRVEEDTKVNSTVIPETQLQAEDRDKDDILFYTLQEMTAGASDYFSLVSV
  NRPALRLDRPLDFYERPNMTFWLLVRDTPGENVEPSHTATATLVLNVVPADLRPPWFLPC
  TFSDGYVCIQAQYHGAVPTGHILPSPLVLRPGPIYAEDGDRGINQPIIYSIFRGNVNGTF
  IIHPDSGNLTVARSVPSPMTFLLLVKGQQADLARYSVTQVTVEAVAAAGSPPRFPQRLYR
  GTVARGAGAGVVVKDAAAPSQPLRIQAQDPEFSDLNSAITYRITNHSHFRMEGEVVLTTT
  TLAQAGAFYAEVEAHNTVTSGTATTVIEIQVSEQEPPSTDVPPSPEAGGTTGPWTSTTSE
  VPRPPEPSQGPSTTSSGGGTGPHPPSGTTLRPPTSSTPGGPPGAENSTSHQPATPGGDTA
  QTPKPGTSQPMPPGVGTSTSHQPATPSGGTAQTPEPGTSQPMPPSMGTSTSHQPATPGGG
  TAQTPEAGTSQPMPPGMGTSTSHQPTTPGGGTAQTPEPGTSQPMPLSKSTPSSGGGPSED
  KRFSVVDMAALGGVLGALLLLALLGLAVLVHKHYGPRLKCCCGKAPEPQPQGFDNQAFLP
  DHKANWAPVPSPTHDPKPAEAPMPAEPAPPGPASPGGAPEPPAAARAGGSPTAVRSILTK
  ERRPEGGYKAVWFGEDIGTEADVVVLNAPTLDVDGASDSGSGDEGEGAGRGGGPYDAPGG
  DDSYI
• Function: Intermicrovillar adhesion molecule that forms, via its extracellular domain, calcium-dependent heterophilic complexes with CDHR2 on adjacent microvilli. Thereby, controls the packing of microvilli at the apical membrane of epithelial cells. Through its cytoplasmic domain, interacts with microvillus cytoplasmic proteins to form the intermicrovillar adhesion complex/IMAC. This complex plays a central role in microvilli and epithelial brush border differentiation.
• Tissue Specificity: Highest expression in kidney, liver, colon and small intestine. In kidney, expressed apically along brush border of proximal convoluted tubule but not in cortical collecting ducts. Isoform 1 is expressed primarily in adult small intestine and colon. Isoform 2 is highly expressed in fetal liver . Expressed in duodenum with higher expression in enterocytes along the villus axis and lower expression in crypts (at protein level) .

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant polycystic kidney disease	DISBHWUI	Strong	Biomarker	[1]
Cholelithiasis	DISERLZB	Strong	Genetic Variation	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Altered Expression	[3]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Gerstmann-Straussler-Scheinker syndrome	DISIO6KC	Strong	Genetic Variation	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[5]
Hereditary nonpolyposis colon cancer	DISPA49R	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[3]
Systemic sclerosis	DISF44L6	Strong	Genetic Variation	[6]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[7]

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 Cadherin-related family member 5 (CDHR5).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Cadherin-related family member 5 (CDHR5).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Cadherin-related family member 5 (CDHR5).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Cadherin-related family member 5 (CDHR5).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Cadherin-related family member 5 (CDHR5).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Cadherin-related family member 5 (CDHR5).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cadherin-related family member 5 (CDHR5).	[14]

References

• [1] Epigenetic silencing of the MUPCDH gene as a possible prognostic biomarker for cyst growth in ADPKD.Sci Rep. 2015 Oct 14;5:15238. doi: 10.1038/srep15238.
• [2] Polymorphism at the mucin-like protocadherin gene influences susceptibility to gallstone disease.Clin Chim Acta. 2011 Nov 20;412(23-24):2089-93. doi: 10.1016/j.cca.2011.07.015. Epub 2011 Aug 1.
• [3] Loss of cadherin related family member 5 (CDHR5) expression in clear cell renal cell carcinoma is a prognostic marker of disease progression.Oncotarget. 2017 Aug 24;8(43):75076-75086. doi: 10.18632/oncotarget.20507. eCollection 2017 Sep 26.
• [4] Loss of expression of -protocadherin and protocadherin-24 in sporadic and hereditary nonpolyposis colorectal cancers.Hum Pathol. 2019 Feb;84:299-308. doi: 10.1016/j.humpath.2018.09.019. Epub 2018 Oct 5.
• [5] CDHR5 inhibits proliferation of hepatocellular carcinoma and predicts clinical prognosis.Ir J Med Sci. 2020 May;189(2):439-447. doi: 10.1007/s11845-019-02092-7. Epub 2019 Sep 3.
• [6] GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways.Nat Commun. 2019 Oct 31;10(1):4955. doi: 10.1038/s41467-019-12760-y.
• [7] Transancestral mapping and genetic load in systemic lupus erythematosus.Nat Commun. 2017 Jul 17;8:16021. doi: 10.1038/ncomms16021.
• [8] 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.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] 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.