Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7KDEL3)

• DOT Name: Protocadherin-1 (PCDH1)
• Synonyms: Cadherin-like protein 1; Protocadherin-42; PC42
• Gene Name: PCDH1
• Related Disease:
  Hantavirus infection
  Allergic asthma
  Atopic dermatitis
  Craniosynostosis
  Matthew-Wood syndrome
• UniProt ID: PCDH1_HUMAN
• PDB ID: 6BX7; 6MGA; 6PIM; 6VFP
• Pfam ID: PF00028 ; PF08266 ; PF08374
• Sequence:
  MDSGAGGRRCPEAALLILGPPRMEHLRHSPGPGGQRLLLPSMLLALLLLLAPSPGHATRV
  VYKVPEEQPPNTLIGSLAADYGFPDVGHLYKLEVGAPYLRVDGKTGDIFTTETSIDREGL
  RECQNQLPGDPCILEFEVSITDLVQNGSPRLLEGQIEVQDINDNTPNFASPVITLAIPEN
  TNIGSLFPIPLASDRDAGPNGVASYELQAGPEAQELFGLQVAEDQEEKQPQLIVMGNLDR
  ERWDSYDLTIKVQDGGSPPRASSALLRVTVLDTNDNAPKFERPSYEAELSENSPIGHSVI
  QVKANDSDQGANAEIEYTFHQAPEVVRRLLRLDRNTGLITVQGPVDREDLSTLRFSVLAK
  DRGTNPKSARAQVVVTVKDMNDNAPTIEIRGIGLVTHQDGMANISEDVAEETAVALVQVS
  DRDEGENAAVTCVVAGDVPFQLRQASETGSDSKKKYFLQTTTPLDYEKVKDYTIEIVAVD
  SGNPPLSSTNSLKVQVVDVNDNAPVFTQSVTEVAFPENNKPGEVIAEITASDADSGSNAE
  LVYSLEPEPAAKGLFTISPETGEIQVKTSLDREQRESYELKVVAADRGSPSLQGTATVLV
  NVLDCNDNDPKFMLSGYNFSVMENMPALSPVGMVTVIDGDKGENAQVQLSVEQDNGDFVI
  QNGTGTILSSLSFDREQQSTYTFQLKAVDGGVPPRSAYVGVTINVLDENDNAPYITAPSN
  TSHKLLTPQTRLGETVSQVAAEDFDSGVNAELIYSIAGGNPYGLFQIGSHSGAITLEKEI
  ERRHHGLHRLVVKVSDRGKPPRYGTALVHLYVNETLANRTLLETLLGHSLDTPLDIDIAG
  DPEYERSKQRGNILFGVVAGVVAVALLIALAVLVRYCRQREAKSGYQAGKKETKDLYAPK
  PSGKASKGNKSKGKKSKSPKPVKPVEDEDEAGLQKSLKFNLMSDAPGDSPRIHLPLNYPP
  GSPDLGRHYRSNSPLPSIQLQPQSPSASKKHQVVQDLPPANTFVGTGDTTSTGSEQYSDY
  SYRTNPPKYPSKQVGQPFQLSTPQPLPHPYHGAIWTEVWE
• Function: May be involved in cell-cell interaction processes and in cell adhesion.
• Tissue Specificity: Highly expressed in the brain and neuro-glial cells.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hantavirus infection	DISZFTMH	Definitive	Biomarker	[1]
Allergic asthma	DISHF0H3	Strong	Genetic Variation	[2]
Atopic dermatitis	DISTCP41	Strong	Genetic Variation	[3]
Craniosynostosis	DIS6J405	Strong	Altered Expression	[4]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Protocadherin-1 (PCDH1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protocadherin-1 (PCDH1).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protocadherin-1 (PCDH1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protocadherin-1 (PCDH1).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Protocadherin-1 (PCDH1).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Protocadherin-1 (PCDH1).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Protocadherin-1 (PCDH1).	[11]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Protocadherin-1 (PCDH1).	[12]
Epanova	DMHEAGL	Approved	Epanova decreases the expression of Protocadherin-1 (PCDH1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protocadherin-1 (PCDH1).	[14]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Protocadherin-1 (PCDH1).	[15]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Protocadherin-1 (PCDH1).	[6]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Protocadherin-1 (PCDH1).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protocadherin-1 (PCDH1).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Protocadherin-1 (PCDH1).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protocadherin-1 (PCDH1).	[20]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Protocadherin-1 (PCDH1).	[21]
Hydroxydimethylarsine Oxide	DMPS2B1	Investigative	Hydroxydimethylarsine Oxide decreases the expression of Protocadherin-1 (PCDH1).	[22]

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 decreases the methylation of Protocadherin-1 (PCDH1).	[17]

References

• [1] Hantavirus entry: Perspectives and recent advances.Adv Virus Res. 2019;104:185-224. doi: 10.1016/bs.aivir.2019.07.002. Epub 2019 Aug 7.
• [2] Genetic variants in Protocadherin-1, bronchial hyper-responsiveness, and asthma subphenotypes in German children.Pediatr Allergy Immunol. 2012 Nov;23(7):636-41. doi: 10.1111/j.1399-3038.2012.01334.x. Epub 2012 Oct 11.
• [3] The PCDH1 gene and asthma in early childhood.Eur Respir J. 2014 Mar;43(3):792-800. doi: 10.1183/09031936.00021613. Epub 2013 Aug 29.
• [4] Protocadherin-1 is a glucocorticoid-responsive critical regulator of airway epithelial barrier function.BMC Pulm Med. 2015 Jul 31;15:80. doi: 10.1186/s12890-015-0078-z.
• [5] Identification and Validation of Novel Subtype-Specific Protein Biomarkers in Pancreatic Ductal Adenocarcinoma.Pancreas. 2017 Mar;46(3):311-322. doi: 10.1097/MPA.0000000000000743.
• [6] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [7] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [8] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [13] Differential effects of omega-3 and omega-6 Fatty acids on gene expression in breast cancer cells. Breast Cancer Res Treat. 2007 Jan;101(1):7-16. doi: 10.1007/s10549-006-9269-x. Epub 2006 Jul 6.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [16] 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.
• [17] 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.
• [18] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] 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.
• [22] Identification of interspecies concordance of mechanisms of arsenic-induced bladder cancer. Toxicol In Vitro. 2007 Dec;21(8):1513-29. doi: 10.1016/j.tiv.2007.06.021. Epub 2007 Jul 21.