Details of Drug Off-Target (DOT)

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

• DOT Name: PDZ domain-containing protein 2 (PDZD2)
• Synonyms: Activated in prostate cancer protein; PDZ domain-containing protein 3
• Gene Name: PDZD2
• Related Disease:
  Alzheimer disease
  Bone osteosarcoma
  Cholangitis
  Inflammation
  Insulinoma
  Major depressive disorder
  Neoplasm
  Osteosarcoma
  Pancreatitis
  Primary biliary cholangitis
  Primary sclerosing cholangitis
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Renal cell carcinoma
  Acute myelogenous leukaemia
  Clear cell renal carcinoma
  Myocardial infarction
  Chronic obstructive pulmonary disease
• UniProt ID: PDZD2_HUMAN
• Pfam ID: PF00595
• Sequence:
  MPITQDNAVLHLPLLYQWLQNSLQEGGDGPEQRLCQAAIQKLQEYIQLNFAVDESTVPPD
  HSPPEMEICTVYLTKELGDTETVGLSFGNIPVFGDYGEKRRGGKKRKTHQGPVLDVGCIW
  VTELRKNSPAGKSGKVRLRDEILSLNGQLMVGVDVSGASYLAEQCWNGGFIYLIMLRRFK
  HKAHSTYNGNSSNSSEPGETPTLELGDRTAKKGKRTRKFGVISRPPANKAPEESKGSAGC
  EVSSDPSTELENGPDPELGNGHVFQLENGPDSLKEVAGPHLERSEVDRGTEHRIPKTDAP
  LTTSNDKRRFSKGGKTDFQSSDCLAREEVGRIWKMELLKESDGLGIQVSGGRGSKRSPHA
  IVVTQVKEGGAAHRDGRLSLGDELLVINGHLLVGLSHEEAVAILRSATGMVQLVVASKEN
  SAEDLLRLTSKSLPDLTSSVEDVSSWTDNEDQEADGEEDEGTSSSVQRAMPGTDEPQDVC
  GAEESKGNLESPKQGSNKIKLKSRLSGGVHRLESVEEYNELMVRNGDPRIRMLEVSRDGR
  KHSLPQLLDSSSASQEYHIVKKSTRSLSTTQVESPWRLIRPSVISIIGLYKEKGKGLGFS
  IAGGRDCIRGQMGIFVKTIFPNGSAAEDGRLKEGDEILDVNGIPIKGLTFQEAIHTFKQI
  RSGLFVLTVRTKLVSPSLTPCSTPTHMSRSASPNFNTSGGASAGGSDEGSSSSLGRKTPG
  PKDRIVMEVTLNKEPRVGLGIGACCLALENSPPGIYIHSLAPGSVAKMESNLSRGDQILE
  VNSVNVRHAALSKVHAILSKCPPGPVRLVIGRHPNPKVSEQEMDEVIARSTYQESKEANS
  SPGLGTPLKSPSLAKKDSLISESELSQYFAHDVPGPLSDFMVAGSEDEDHPGSGCSTSEE
  GSLPPSTSTHKEPGKPRANSLVTLGSHRASGLFHKQVTVARQASLPGSPQALRNPLLRQR
  KVGCYDANDASDEEEFDREGDCISLPGALPGPIRPLSEDDPRRVSISSSKGMDVHNQEER
  PRKTLVSKAISAPLLGSSVDLEESIPEGMVDAASYAANLTDSAEAPKGSPGSWWKKELSG
  SSSAPKLEYTVRTDTQSPTNTGSPSSPQQKSEGLGSRHRPVARVSPHCKRSEAEAKPSGS
  QTVNLTGRANDPCDLDSRVQATSVKVTVAGFQPGGAVEKESLGKLTTGDACVSTSCELAS
  ALSHLDASHLTENLPKAASELGQQPMTELDSSSDLISSPGKKGAAHPDPSKTSVDTGQVS
  RPENPSQPASPRVTKCKARSPVRLPHEGSPSPGEKAAAPPDYSKTRSASETSTPHNTRRV
  AALRGAGPGAEGMTPAGAVLPGDPLTSQEQRQGAPGNHSKALEMTGIHAPESSQEPSLLE
  GADSVSSRAPQASLSMLPSTDNTKEACGHVSGHCCPGGSRESPVTDIDSFIKELDASAAR
  SPSSQTGDSGSQEGSAQGHPPAGAGGGSSCRAEPVPGGQTSSPRRAWAAGAPAYPQWASQ
  PSVLDSINPDKHFTVNKNFLSNYSRNFSSFHEDSTSLSGLGDSTEPSLSSMYGDAEDSSS
  DPESLTEAPRASARDGWSPPRSRVSLHKEDPSESEEEQIEICSTRGCPNPPSSPAHLPTQ
  AAICPASAKVLSLKYSTPRESVASPREKAACLPGSYTSGPDSSQPSSLLEMSSQEHETHA
  DISTSQNHRPSCAEETTEVTSASSAMENSPLSKVARHFHSPPIILSSPNMVNGLEHDLLD
  DETLNQYETSINAAASLSSFSVDVPKNGESVLENLHISESQDLDDLLQKPKMIARRPIMA
  WFKEINKHNQGTHLRSKTEKEQPLMPARSPDSKIQMVSSSQKKGVTVPHSPPQPKTNLEN
  KDLSKKSPAEMLLTNGQKAKCGPKLKRLSLKGKAKVNSEAPAANAVKAGGTDHRKPLISP
  QTSHKTLSKAVSQRLHVADHEDPDRNTTAAPRSPQCVLESKPPLATSGPLKPSVSDTSIR
  TFVSPLTSPKPVPEQGMWSRFHMAVLSEPDRGCPTTPKSPKCRAEGRAPRADSGPVSPAA
  SRNGMSVAGNRQSEPRLASHVAADTAQPRPTGEKGGNIMASDRLERTNQLKIVEISAEAV
  SETVCGNKPAESDRRGGCLAQGNCQEKSEIRLYRQVAESSTSHPSSLPSHASQAEQEMSR
  SFSMAKLASSSSSLQTAIRKAEYSQGKSSLMSDSRGVPRNSIPGGPSGEDHLYFTPRPAT
  RTYSMPAQFSSHFGREGHPPHSLGRSRDSQVPVTSSVVPEAKASRGGLPSLANGQGIYSV
  KPLLDTSRNLPATDEGDIISVQETSCLVTDKIKVTRRHYCYEQNWPHESTSFFSVKQRIK
  SFENLANADRPVAKSGASPFLSVSSKPPIGRRSSGSIVSGSLGHPGDAAARLLRRSLSSC
  SENQSEAGTLLPQMAKSPSIMTLTISRQNPPETSSKGSDSELKKSLGPLGIPTPTMTLAS
  PVKRNKSSVRHTQPSPVSRSKLQELRALSMPDLDKLCSEDYSAGPSAVLFKTELEITPRR
  SPGPPAGGVSCPEKGGNRACPGGSGPKTSAAETPSSASDTGEAAQDLPFRRSWSVNLDQL
  LVSAGDQQRLQSVLSSVGSKSTILTLIQEAKAQSENEEDVCFIVLNRKEGSGLGFSVAGG
  TDVEPKSITVHRVFSQGAASQEGTMNRGDFLLSVNGASLAGLAHGNVLKVLHQAQLHKDA
  LVVIKKGMDQPRPSARQEPPTANGKGLLSRKTIPLEPGIGRSVAVHDALCVEVLKTSAGL
  GLSLDGGKSSVTGDGPLVIKRVYKGGAAEQAGIIEAGDEILAINGKPLVGLMHFDAWNIM
  KSVPEGPVQLLIRKHRNSS
• Tissue Specificity: Isoform 2 is expressed (at protein level) in prostate and many prostate tumors.

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[2]
Cholangitis	DIS9U3YN	Strong	Biomarker	[3]
Inflammation	DISJUQ5T	Strong	Biomarker	[3]
Insulinoma	DISIU1JS	Strong	Biomarker	[2]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[2]
Pancreatitis	DIS0IJEF	Strong	Biomarker	[3]
Primary biliary cholangitis	DIS43E0O	Strong	Biomarker	[3]
Primary sclerosing cholangitis	DISTH5WJ	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[6]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[7]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[8]
Clear cell renal carcinoma	DISBXRFJ	moderate	Genetic Variation	[9]
Myocardial infarction	DIS655KI	moderate	Genetic Variation	[10]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Genetic Variation	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of PDZ domain-containing protein 2 (PDZD2).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of PDZ domain-containing protein 2 (PDZD2).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of PDZ domain-containing protein 2 (PDZD2).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of PDZ domain-containing protein 2 (PDZD2).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of PDZ domain-containing protein 2 (PDZD2).	[17]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of PDZ domain-containing protein 2 (PDZD2).	[18]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of PDZ domain-containing protein 2 (PDZD2).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of PDZ domain-containing protein 2 (PDZD2).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of PDZ domain-containing protein 2 (PDZD2).	[23]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of PDZ domain-containing protein 2 (PDZD2).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of PDZ domain-containing protein 2 (PDZD2).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of PDZ domain-containing protein 2 (PDZD2).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of PDZ domain-containing protein 2 (PDZD2).	[21]

References

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• [2] miR-363 acts as a tumor suppressor in osteosarcoma cells by inhibiting PDZD2.Oncol Rep. 2019 May;41(5):2729-2738. doi: 10.3892/or.2019.7078. Epub 2019 Mar 19.
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• [4] Citalopram and escitalopram plasma drug and metabolite concentrations: genome-wide associations.Br J Clin Pharmacol. 2014 Aug;78(2):373-83. doi: 10.1111/bcp.12348.
• [5] Pre-clinical and clinical evaluation of estramustine, docetaxel and thalidomide combination in androgen-independent prostate cancer.BJU Int. 2007 May;99(5):1047-55. doi: 10.1111/j.1464-410X.2007.06763.x.
• [6] Activated in prostate cancer: a PDZ domain-containing protein highly expressed in human primary prostate tumors.Cancer Res. 2001 Mar 15;61(6):2390-4.
• [7] Common variation at 2q22.3 (ZEB2) influences the risk of renal cancer.Hum Mol Genet. 2013 Feb 15;22(4):825-31. doi: 10.1093/hmg/dds489. Epub 2012 Nov 25.
• [8] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [9] Germline genetic variations in PDZD2 and ITPR2 genes are associated with clear cell renal cell carcinoma in Chinese population.Oncotarget. 2017 Apr 11;8(15):24196-24201. doi: 10.18632/oncotarget.6917.
• [10] A genome-wide association study reveals susceptibility loci for myocardial infarction/coronary artery disease in Saudi Arabs.Atherosclerosis. 2016 Feb;245:62-70. doi: 10.1016/j.atherosclerosis.2015.11.019. Epub 2015 Nov 22.
• [11] A Genome-Wide Association Study in Hispanics/Latinos Identifies Novel Signals for Lung Function. The Hispanic Community Health Study/Study of Latinos.Am J Respir Crit Care Med. 2018 Jul 15;198(2):208-219. doi: 10.1164/rccm.201707-1493OC.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [17] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [18] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [19] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [20] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [21] 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.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [24] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.