Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP091X8)

• DOT Name: Protocadherin-7 (PCDH7)
• Synonyms: Brain-heart protocadherin; BH-Pcdh
• Gene Name: PCDH7
• Related Disease:
  Breast cancer
  Castration-resistant prostate carcinoma
  Epilepsy
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Neoplasm
  Non-small-cell lung cancer
  Prostate cancer
  Prostate carcinoma
  Schizophrenia
  Urinary bladder cancer
  Urinary bladder neoplasm
  Breast carcinoma
  Gastric cancer
  Neuroblastoma
  Rett syndrome
  Stomach cancer
• UniProt ID: PCDH7_HUMAN
• PDB ID: 2YST
• Pfam ID: PF00028 ; PF08266 ; PF08374
• Sequence:
  MLRMRTAGWARGWCLGCCLLLPLSLSLAAAKQLLRYRLAEEGPADVRIGNVASDLGIVTG
  SGEVTFSLESGSEYLKIDNLTGELSTSERRIDREKLPQCQMIFDENECFLDFEVSVIGPS
  QSWVDLFEGQVIVLDINDNTPTFPSPVLTLTVEENRPVGTLYLLPTATDRDFGRNGIERY
  ELLQEPGGGGSGGESRRAGAADSAPYPGGGGNGASGGGSGGSKRRLDASEGGGGTNPGGR
  SSVFELQVADTPDGEKQPQLIVKGALDREQRDSYELTLRVRDGGDPPRSSQAILRVLITD
  VNDNSPRFEKSVYEADLAENSAPGTPILQLRAADLDVGVNGQIEYVFGAATESVRRLLRL
  DETSGWLSVLHRIDREEVNQLRFTVMARDRGQPPKTDKATVVLNIKDENDNVPSIEIRKI
  GRIPLKDGVANVAEDVLVDTPIALVQVSDRDQGENGVVTCTVVGDVPFQLKPASDTEGDQ
  NKKKYFLHTSTPLDYEATREFNVVIVAVDSGSPSLSSNNSLIVKVGDTNDNPPMFGQSVV
  EVYFPENNIPGERVATVLATDADSGKNAEIAYSLDSSVMGIFAIDPDSGDILVNTVLDRE
  QTDRYEFKVNAKDKGIPVLQGSTTVIVQVADKNDNDPKFMQDVFTFYVKENLQPNSPVGM
  VTVMDADKGRNAEMSLYIEENNNIFSIENDTGTIYSTMSFDREHQTTYTFRVKAVDGGDP
  PRSATATVSLFVMDENDNAPTVTLPKNISYTLLPPSSNVRTVVATVLATDSDDGINADLN
  YSIVGGNPFKLFEIDPTSGVVSLVGKLTQKHYGLHRLVVQVNDSGQPSQSTTTLVHVFVN
  ESVSNATAIDSQIARSLHIPLTQDIAGDPSYEISKQRLSIVIGVVAGIMTVILIILIVVM
  ARYCRSKNKNGYEAGKKDHEDFFTPQQHDKSKKPKKDKKNKKSKQPLYSSIVTVEASKPN
  GQRYDSVNEKLSDSPSMGRYRSVNGGPGSPDLARHYKSSSPLPTVQLHPQSPTAGKKHQA
  VQDLPPANTFVGAGDNISIGSDHCSEYSCQTNNKYSKQMRLHPYITVFG
• Tissue Specificity: Expressed predominantly in brain and heart and at lower levels in various other tissues.
• Reactome Pathway:
  RHOA GTPase cycle (R-HSA-8980692)
  RHOB GTPase cycle (R-HSA-9013026)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Biomarker	[2]
Epilepsy	DISBB28L	Strong	Biomarker	[3]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[1]
Lung cancer	DISCM4YA	Strong	Biomarker	[1]
Lung carcinoma	DISTR26C	Strong	Biomarker	[1]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[2]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[2]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[5]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[1]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[7]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[8]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[9]
Rett syndrome	DISGG5UV	Limited	Biomarker	[9]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[8]

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 Protocadherin-7 (PCDH7).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protocadherin-7 (PCDH7).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protocadherin-7 (PCDH7).	[24]

16 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-7 (PCDH7).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protocadherin-7 (PCDH7).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protocadherin-7 (PCDH7).	[13]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protocadherin-7 (PCDH7).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Protocadherin-7 (PCDH7).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Protocadherin-7 (PCDH7).	[16]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Protocadherin-7 (PCDH7).	[17]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Protocadherin-7 (PCDH7).	[16]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Protocadherin-7 (PCDH7).	[18]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Protocadherin-7 (PCDH7).	[19]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Protocadherin-7 (PCDH7).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protocadherin-7 (PCDH7).	[22]
NS398	DMINUWH	Terminated	NS398 increases the expression of Protocadherin-7 (PCDH7).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protocadherin-7 (PCDH7).	[25]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Protocadherin-7 (PCDH7).	[26]
Manganese	DMKT129	Investigative	Manganese increases the expression of Protocadherin-7 (PCDH7).	[27]

References

• [1] Modulation of Mutant Kras(G12D) -Driven Lung Tumorigenesis In Vivo by Gain or Loss of PCDH7 Function.Mol Cancer Res. 2019 Feb;17(2):594-603. doi: 10.1158/1541-7786.MCR-18-0739. Epub 2018 Nov 8.
• [2] Protocadherin 7 is overexpressed in castration resistant prostate cancer and promotes aberrant MEK and AKT signaling.Prostate. 2019 Nov;79(15):1739-1751. doi: 10.1002/pros.23898. Epub 2019 Aug 26.
• [3] Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies.Lancet Neurol. 2014 Sep;13(9):893-903. doi: 10.1016/S1474-4422(14)70171-1. Epub 2014 Jul 30.
• [4] PROTOCADHERIN 7 Acts through SET and PP2A to Potentiate MAPK Signaling by EGFR and KRAS during Lung Tumorigenesis.Cancer Res. 2017 Jan 1;77(1):187-197. doi: 10.1158/0008-5472.CAN-16-1267-T. Epub 2016 Nov 7.
• [5] Five novel loci associated with antipsychotic treatment response in patients with schizophrenia: a genome-wide association study.Lancet Psychiatry. 2018 Apr;5(4):327-338. doi: 10.1016/S2215-0366(18)30049-X. Epub 2018 Mar 1.
• [6] Hypermethylation of the polycomb group target gene PCDH7 in bladder tumors from patients of all ages.J Urol. 2013 Jul;190(1):311-6. doi: 10.1016/j.juro.2013.01.078. Epub 2013 Jan 28.
• [7] Protocadherin-7 induces bone metastasis of breast cancer.Biochem Biophys Res Commun. 2013 Jul 5;436(3):486-90. doi: 10.1016/j.bbrc.2013.05.131. Epub 2013 Jun 7.
• [8] Asymmetric dimethylation at histone H3 arginine 2 by PRMT6 in gastric cancer progression.Carcinogenesis. 2019 Mar 12;40(1):15-26. doi: 10.1093/carcin/bgy147.
• [9] The protocadherins, PCDHB1 and PCDH7, are regulated by MeCP2 in neuronal cells and brain tissues: implication for pathogenesis of Rett syndrome.BMC Neurosci. 2011 Aug 8;12:81. doi: 10.1186/1471-2202-12-81.
• [10] Nuclear and Mitochondrial DNA Methylation Patterns Induced by Valproic Acid in Human Hepatocytes. Chem Res Toxicol. 2017 Oct 16;30(10):1847-1854. doi: 10.1021/acs.chemrestox.7b00171. Epub 2017 Sep 13.
• [11] 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.
• [12] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [13] Real-time monitoring of cisplatin-induced cell death. PLoS One. 2011;6(5):e19714. doi: 10.1371/journal.pone.0019714. Epub 2011 May 16.
• [14] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [15] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [16] 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.
• [17] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [18] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [23] Detection of differentially expressed genes in human colon carcinoma cells treated with a selective COX-2 inhibitor. Oncogene. 2001 Jul 27;20(33):4450-6. doi: 10.1038/sj.onc.1204588.
• [24] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [25] 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.
• [26] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [27] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.