Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX3BFV4)

• DOT Name: Protocadherin-9 (PCDH9)
• Gene Name: PCDH9
• Related Disease:
  Auditory neuropathy
  Autosomal dominant auditory neuropathy 1
  Advanced cancer
  Autism
  Autism spectrum disorder
  Chronic obstructive pulmonary disease
  Epithelial ovarian cancer
  Glioma
  Hepatocellular carcinoma
  Major depressive disorder
  Malignant glioma
  Obesity
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Hirschsprung disease
  Neoplasm
  Gastric cancer
  Stomach cancer
• UniProt ID: PCDH9_HUMAN
• PDB ID: 2EE0
• Pfam ID: PF00028 ; PF08266 ; PF08374
• Sequence:
  MDLRDFYLLAALIACLRLDSAIAQELIYTIREELPENVPIGNIPKDLNISHINAATGTSA
  SLVYRLVSKAGDAPLVKVSSSTGEIFTTSNRIDREKLCAGASYAEENECFFELEVVILPN
  DFFRLIKIKIIVKDTNDNAPMFPSPVINISIPENTLINSRFPIPSATDPDTGFNGVQHYE
  LLNGQSVFGLDIVETPEGEKWPQLIVQQNLDREQKDTYVMKIKVEDGGTPQKSSTAILQV
  TVSDVNDNRPVFKEGQVEVHIPENAPVGTSVIQLHATDADIGSNAEIRYIFGAQVAPATK
  RLFALNNTTGLITVQRSLDREETAIHKVTVLASDGSSTPARATVTINVTDVNDNPPNIDL
  RYIISPINGTVYLSEKDPVNTKIALITVSDKDTDVNGKVICFIEREVPFHLKAVYDNQYL
  LETSSLLDYEGTKEFSFKIVASDSGKPSLNQTALVRVKLEDENDNPPIFNQPVIELSVSE
  NNRRGLYLTTISATDEDSGKNADIVYQLGPNASFFDLDRKTGVLTASRVFDREEQERFIF
  TVTARDNGTPPLQSQAAVIVTVLDENDNSPKFTHNHFQFFVSENLPKYSTVGVITVTDAD
  AGENKAVTLSILNDNDNFVLDPYSGVIKSNVSFDREQQSSYTFDVKATDGGQPPRSSTAK
  VTINVMDVNDNSPVVISPPSNTSFKLVPLSAIPGSVVAEVFAVDVDTGMNAELKYTIVSG
  NNKGLFRIDPVTGNITLEEKPAPTDVGLHRLVVNISDLGYPKSLHTLVLVFLYVNDTAGN
  ASYIYDLIRRTMETPLDRNIGDSSQPYQNEDYLTIMIAIIAGAMVVIVVIFVTVLVRCRH
  ASRFKAAQRSKQGAEWMSPNQENKQNKKKKRKKRKSPKSSLLNFVTIEESKPDDAVHEPI
  NGTISLPAELEEQSIGRFDWGPAPPTTFKPNSPDLAKHYKSASPQPAFHLKPDTPVSVKK
  HHVIQELPLDNTFVGGCDTLSKRSSTSSDHFSASECSSQGGFKTKGPLHTRQCNSHSKSD
  NIPVTPQKCPSSTGFHIQENEESHYESQRRVTFHLPDGSQESCSDSGLGDHEPVGSGTLI
  SHPLPLVQPQDEFYDQASPDKRTEADGNSDPNSDGPLGPRGLAEATEMCTQECLVLGHSD
  NCWMPPGLGPYQHPKSPLSTFAPQKEWVKKDKLVNGHTLTRAWKEDSNRNQFNDRKQYGS
  NEGHFNNGSHMTDIPLANLKSYKQAGGATESPKEHQL
• Function: Potential calcium-dependent cell-adhesion protein.

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Auditory neuropathy	DISM6GAU	Definitive	Genetic Variation	[1]
Autosomal dominant auditory neuropathy 1	DISPY0YJ	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Autism	DISV4V1Z	Strong	Biomarker	[3]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[4]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[6]
Glioma	DIS5RPEH	Strong	Altered Expression	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[8]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[9]
Malignant glioma	DISFXKOV	Strong	Altered Expression	[7]
Obesity	DIS47Y1K	Strong	Genetic Variation	[10]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[6]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[6]
Prostate cancer	DISF190Y	Strong	Biomarker	[11]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[11]
Hirschsprung disease	DISUUSM1	moderate	Biomarker	[12]
Neoplasm	DISZKGEW	moderate	Biomarker	[11]
Gastric cancer	DISXGOUK	Limited	Biomarker	[2]
Stomach cancer	DISKIJSX	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Protocadherin-9 (PCDH9).	[13]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protocadherin-9 (PCDH9).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protocadherin-9 (PCDH9).	[24]

12 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 Protocadherin-9 (PCDH9).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protocadherin-9 (PCDH9).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Protocadherin-9 (PCDH9).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protocadherin-9 (PCDH9).	[17]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Protocadherin-9 (PCDH9).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Protocadherin-9 (PCDH9).	[20]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Protocadherin-9 (PCDH9).	[21]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protocadherin-9 (PCDH9).	[22]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Protocadherin-9 (PCDH9).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protocadherin-9 (PCDH9).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protocadherin-9 (PCDH9).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Protocadherin-9 (PCDH9).	[27]

References

• [1] Pure monosomy and pure trisomy of 13q21.2-31.1 consequent to a familial insertional translocation: exclusion of PCDH9 as the responsible gene for autosomal dominant auditory neuropathy (AUNA1).Am J Med Genet A. 2009 May;149A(5):906-13. doi: 10.1002/ajmg.a.32754.
• [2] Loss of PCDH9 is associated with the differentiation of tumor cells and metastasis and predicts poor survival in gastric cancer.Clin Exp Metastasis. 2015 Jun;32(5):417-28. doi: 10.1007/s10585-015-9712-7. Epub 2015 Apr 14.
• [3] A genome-wide survey of transgenerational genetic effects in autism.PLoS One. 2013 Oct 24;8(10):e76978. doi: 10.1371/journal.pone.0076978. eCollection 2013.
• [4] Structural variation of chromosomes in autism spectrum disorder.Am J Hum Genet. 2008 Feb;82(2):477-88. doi: 10.1016/j.ajhg.2007.12.009. Epub 2008 Jan 17.
• [5] The genetics of smoking in individuals with chronic obstructive pulmonary disease.Respir Res. 2018 Apr 10;19(1):59. doi: 10.1186/s12931-018-0762-7.
• [6] MiR-200a-3p promoted the malignant behaviors of ovarian cancer cells through regulating PCDH9.Onco Targets Ther. 2019 Oct 8;12:8329-8338. doi: 10.2147/OTT.S220339. eCollection 2019.
• [7] Dual inhibition of PCDH9 expression by miR-215-5p up-regulation in gliomas.Oncotarget. 2017 Feb 7;8(6):10287-10297. doi: 10.18632/oncotarget.14396.
• [8] Genomewide association study for C-reactive protein in Indians replicates known associations of common variants.J Genet. 2019 Mar;98:20.
• [9] Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions.Nat Neurosci. 2019 Mar;22(3):343-352. doi: 10.1038/s41593-018-0326-7. Epub 2019 Feb 4.
• [10] A genome-wide association study on obesity and obesity-related traits.PLoS One. 2011 Apr 28;6(4):e18939. doi: 10.1371/journal.pone.0018939.
• [11] Whole-genome and Transcriptome Sequencing of Prostate Cancer Identify New Genetic Alterations Driving Disease Progression.Eur Urol. 2018 Mar;73(3):322-339. doi: 10.1016/j.eururo.2017.08.027. Epub 2017 Sep 18.
• [12] Identification of two novel PCDHA9 mutations associated with Hirschsprung's disease.Gene. 2018 Jun 5;658:96-104. doi: 10.1016/j.gene.2018.02.054. Epub 2018 Feb 22.
• [13] 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.
• [14] 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.
• [15] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [16] 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.
• [17] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [18] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [19] 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.
• [20] 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.
• [21] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [24] 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.
• [25] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [26] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [27] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.