Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXJZZ98)

• DOT Name: Protein piccolo (PCLO)
• Synonyms: Aczonin
• Gene Name: PCLO
• Related Disease:
  Advanced cancer
  Bipolar disorder
  Cryopyrin-associated periodic syndrome
  Esophageal squamous cell carcinoma
  Major depressive disorder
  Mental disorder
  Mood disorder
  Pontocerebellar hypoplasia
  Pontocerebellar hypoplasia type 3
  Schizophrenia
  Clear cell renal carcinoma
  Renal cell carcinoma
  Intellectual disability
  Non-insulin dependent diabetes
• UniProt ID: PCLO_HUMAN
• PDB ID: 1UJD
• Pfam ID: PF00168 ; PF00595 ; PF05715
• Sequence:
  MGNEASLEGEGLPEGLAAAAAAGGGASGAGSPSHTAIPAGMEADLSQLSEEERRQIAAVM
  SRAQGLPKGSVPPAAAESPSMHRKQELDSSHPPKQSGRPPDPGRPAQPGLSKSRTTDTFR
  SEQKLPGRSPSTISLKESKSRTDLKEEHKSSMMPGFLSEVNALSAVSSVVNKFNPFDLIS
  DSEASQEETTKKQKVVQKEQGKPEGIIKPPLQQQPPKPIPKQQGPGRDPLQQDGTPKSIS
  SQQPEKIKSQPPGTGKPIQGPTQTPQTDHAKLPLQRDASRPQTKQADIVRGESVKPSLPS
  PSKPPIQQPTPGKPPAQQPGHEKSQPGPAKPPAQPSGLTKPLAQQPGTVKPPVQPPGTTK
  PPAQPLGPAKPPAQQTGSEKPSSEQPGPKALAQPPGVGKTPAQQPGPAKPPTQQVGTPKP
  LAQQPGLQSPAKAPGPTKTPVQQPGPGKIPAQQAGPGKTSAQQTGPTKPPSQLPGPAKPP
  PQQPGPAKPPPQQPGSAKPPSQQPGSTKPPPQQPGPAKPSPQQPGSTKPPSQQPGSAKPS
  AQQPSPAKPSAQQSTKPVSQTGSGKPLQPPTVSPSAKQPPSQGLPKTICPLCNTTELLLH
  VPEKANFNTCTECQTTVCSLCGFNPNPHLTEVKEWLCLNCQMKRALGGDLAPVPSSPQPK
  LKTAPVTTTSAVSKSSPQPQQTSPKKDAAPKQDLSKAPEPKKPPPLVKQPTLHGSPSAKA
  KQPPEADSLSKPAPPKEPSVPSEQDKAPVADDKPKQPKMVKPTTDLVSSSSATTKPDIPS
  SKVQSQAEEKTTPPLKTDSAKPSQSFPPTGEKVSPFDSKAIPRPASDSKIISHPGPSSES
  KGQKQVDPVQKKEEPKKAQTKMSPKPDAKPMPKGSPTPPGPRPTAGQTVPTPQQSPKPQE
  QSRRFSLNLGSITDAPKSQPTTPQETVTGKLFGFGASIFSQASNLISTAGQPGPHSQSGP
  GAPMKQAPAPSQPPTSQGPPKSTGQAPPAPAKSIPVKKETKAPAAEKLEPKAEQAPTVKR
  TETEKKPPPIKDSKSLTAEPQKAVLPTKLEKSPKPESTCPLCKTELNIGSKDPPNFNTCT
  ECKNQVCNLCGFNPTPHLTEIQEWLCLNCQTQRAISGQLGDIRKMPPAPSGPKASPMPVP
  TESSSQKTAVPPQVKLVKKQEQEVKTEAEKVILEKVKETLSMEKIPPMVTTDQKQEESKL
  EKDKASALQEKKPLPEEKKLIPEEEKIRSEEKKPLLEEKKPTPEDKKLLPEAKTSAPEEQ
  KHDLLKSQVQIAEEKLEGRVAPKTVQEGKQPQTKMEGLPSGTPQSLPKEDDKTTKTIKEQ
  PQPPCTAKPDQVEPGKEKTEKEDDKSDTSSSQQPKSPQGLSDTGYSSDGISSSLGEIPSL
  IPTDEKDILKGLKKDSFSQESSPSSPSDLAKLESTVLSILEAQASTLADEKSEKKTQPHE
  VSPEQPKDQEKTQSLSETLEITISEEEIKESQEERKDTFKKDSQQDIPSSKDHKEKSEFV
  DDITTRREPYDSVEESSESENSPVPQRKRRTSVGSSSSDEYKQEDSQGSGEEEDFIRKQI
  IEMSADEDASGSEDDEFIRNQLKEISSSTESQKKEETKGKGKITAGKHRRLTRKSSTSID
  EDAGRRHSWHDEDDEAFDESPELKYRETKSQESEELVVTGGGGLRRFKTIELNSTIADKY
  SAESSQKKTSLYFDEEPELEMESLTDSPEDRSRGEGSSSLHASSFTPGTSPTSVSSLDED
  SDSSPSHKKGESKQQRKARHRPHGPLLPTIEDSSEEEELREEEELLKEQEKQREIEQQQR
  KSSSKKSKKDKDELRAQRRRERPKTPPSNLSPIEDASPTEELRQAAEMEELHRSSCSEYS
  PSIESDPEGFEISPEKIIEVQKVYKLPTAVSLYSPTDEQSIMQKEGSQKALKSAEEMYEE
  MMHKTHKYKAFPAANERDEVFEKEPLYGGMLIEDYIYESLVEDTYNGSVDGSLLTRQEEE
  NGFMQQKGREQKIRLSEQIYEDPMQKITDLQKEFYELESLHSVVPQEDIVSSSFIIPESH
  EIVDLGTMVTSTEEERKLLDADAAYEELMKRQQMQLTPGSSPTQAPIGEDMTESTMDFDR
  MPDASLTSSVLSGASLTDSTSSATLSIPDVKITQHFSTEEIEDEYVTDYTREIQEIIAHE
  SLILTYSEPSESATSVPPSDTPSLTSSVSSVCTTDSSSPITTLDSITTVYTEPVDMITKF
  EDSEEISSSTYFPGSIIDYPEEISVSLDRTAPPDGRASADHIVISLSDMASSIIESVVPK
  PEGPVADTVSTDLLISEKDPVKKAKKETGNGIILEVLEAYRDKKELEAERTKSSLSETVF
  DHPPSSVIALPMKEQLSTTYFTSGETFGQEKPASQLPSGSPSVSSLPAKPRPFFRSSSLD
  ISAQPPPPPPPPPPPPPPPPPPPPPPLPPPTSPKPTILPKKKLTVASPVTTATPLFDAVT
  TLETTAVLRSNGLPVTRICTTAPPPVPPKPSSIPSGLVFTHRPEPSKPPIAPKPVIPQLP
  TTTQKPTDIHPKPTGLSLTSSMTLNLVTSADYKLPSPTSPLSPHSNKSSPRFSKSLTETY
  VVITLPSEPGTPTDSSASQAITSWPLGSPSKDLVSVEPVFSVVPPVTAVEIPISSEQTFY
  ISGALQTFSATPVTAPSSFQAAPTSVTQFLTTEVSKTEVSATRSTAPSVGLSSISITIPP
  EPLALDNIHLEKPQYKEDGKLQLVGDVIDLRTVPKVEVKTTDKCIDLSASTMDVKRQITA
  NEVYGKQISAVQPSIINLSVTSSIVTPVSLATETVTFVTCTASASYTTGTESLVGAEHAM
  TTPLQLTTSKHAEPPYRIPSDQVFPIAREEAPINLSLGTPAHAVTLAITKPVTVPPVGVT
  NGWTDSTVSQGITDGEVVDLSTTKSHRTVVTMDESTSSVMTKIIEDEKPVDLTAGRRAVC
  CDVVYKLPFGRSCTAQQPATTLPEDRFGYRDDHYQYDRSGPYGYRGIGGMKPSMSDTNLA
  EAGHFFYKSKNAFDYSEGTDTAVDLTSGRVTTGEVMDYSSKTTGPYPETRQVISGAGIST
  PQYSTARMTPPPGPQYCVGSVLRSSNGVVYSSVATPTPSTFAITTQPGSIFSTTVRDLSG
  IHTADAVTSLPAMHHSQPMPRSYFITTGASETDIAVTGIDISASLQTITMESLTAETIDS
  VPTLTTASEVFPEVVGDESALLIVPEEDKQQQQLDLERELLELEKIKQQRFAEELEWERQ
  EIQRFREQEKIMVQKKLEELQSMKQHLLFQQEEERQAQFMMRQETLAQQQLQLEQIQQLQ
  QQLHQQLEEQKIRQIYQYNYDPSGTASPQTTTEQAILEGQYAALEGSQFWATEDATTTAS
  AVVAIEIPQSQGWYTVQSDGVTQYIAPPGILSTVSEIPLTDVVVKEEKQPKKRSSGAKVR
  GQYDDMGENMTDDPRSFKKIVDSGVQTDDEDATDRSYVSRRRRTKKSVDTSVQTDDEDQD
  EWDMPTRSRRKARVGKYGDSMTEADKTKPLSKVSSIAVQTVAEISVQTEPVGTIRTPSIR
  ARVDAKVEIIKHISAPEKTYKGGSLGCQTEADSDTQSPQYLSATSPPKDKKRPTPLEIGY
  SSHLRADSTVQLAPSPPKSPKVLYSPISPLSPGKALESAFVPYEKPLPDDISPQKVLHPD
  MAKVPPASPKTAKMMQRSMSDPKPLSPTADESSRAPFQYTEGYTTKGSQTMTSSGAQKKV
  KRTLPNPPPEEISTGTQSTFSTMGTVSRRRICRTNTMARAKILQDIDRELDLVERESAKL
  RKKQAELDEEEKEIDAKLRYLEMGINRRKEALLKEREKRERAYLQGVAEDRDYMSDSEVS
  STRPTRIESQHGIERPRTAPQTEFSQFIPPQTQTESQLVPPTSPYTQYQYSSPALPTQAP
  TSYTQQSHFEQQTLYHQQVSPYQTQPTFQAVATMSFTPQVQPTPTPQPSYQLPSQMMVIQ
  QKPRQTTLYLEPKITSNYEVIRNQPLMIAPVSTDNTFAVSHLGSKYNSLDLRIGLEERSS
  MASSPISSISADSFYADIDHHTPRNYVLIDDIGEITKGTAALSTAFSLHEKDLSKTDRLL
  RTTETRRSQEVTDFLAPLQSSSRLHSYVKAEEDPMEDPYELKLLKHQIKQEFRRGTESLD
  HLAGLSHYYHADTSYRHFPKSEKYSISRLTLEKQAAKQLPAAILYQKQSKHKKSLIDPKM
  SKFSPIQESRDLEPDYSSYMTSSTSSIGGISSRARLLQDDITFGLRKNITDQQKFMGSSL
  GTGLGTLGNTIRSALQDEADKPYSSGSRSRPSSRPSSVYGLDLSIKRDSSSSSLRLKAQE
  AEALDVSFSHASSSARTKPTSLPISQSRGRIPIVAQNSEEESPLSPVGQPMGMARAAAGP
  LPPISADTRDQFGSSHSLPEVQQHMREESRTRGYDRDIAFIMDDFQHAMSDSEAYHLRRE
  ETDWFDKPRESRLENGHGLDRKLPERLVHSRPLSQHQEQIIQMNGKTMHYIFPHARIKIT
  RDSKDHTVSGNGLGIRIVGGKEIPGHSGEIGAYIAKILPGGSAEQTGKLMEGMQVLEWNG
  IPLTSKTYEEVQSIISQQSGEAEICVRLDLNMLSDSENSQHLELHEPPKAVDKAKSPGVD
  PKQLAAELQKVSLQQSPLVLSSVVEKGSHVHSGPTSAGSSSVPSPGQPGSPSVSKKKHGS
  SKPTDGTKVVSHPITGEIQLQINYDLGNLIIHILQARNLVPRDNNGYSDPFVKVYLLPGR
  GQVMVVQNASAEYKRRTKHVQKSLNPEWNQTVIYKSISMEQLKKKTLEVTVWDYDRFSSN
  DFLGEVLIDLSSTSHLDNTPRWYPLKEQTESIDHGKSHSSQSSQQSPKPSVIKSRSHGIF
  PDPSKDMQVPTIEKSHSSPGSSKSSSEGHLRSHGPSRSQSKTSVTQTHLEDAGAAIAAAE
  AAVQQLRIQPTKPPNHRPAESSVSTGSSGSSFGSGYSVDSEGSSSTAGETNLFPIPRIGK
  MGQNGQEPVKQPGVGVGLADTEAKTQVMGEIKIALKKEMKTDGEQLIVEILQCRNITYKF
  KSPDHLPDLYVKIYVMNISTQKKVIKKKTRVCRHDREPSFNETFRFSLSPAGHSLQILLF
  SNGGKFMKKTLIGEACIWLDKVDLRKRIVNWHKLLVSPTQTH
• Function: Scaffold protein of the presynaptic cytomatrix at the active zone (CAZ) which is the place in the synapse where neurotransmitter is released. After synthesis, participates in the formation of Golgi-derived membranous organelles termed Piccolo-Bassoon transport vesicles (PTVs) that are transported along axons to sites of nascent synaptic contacts. At the presynaptic active zone, regulates the spatial organization of synaptic vesicle cluster, the protein complexes that execute membrane fusion and compensatory endocytosis. Organizes as well the readily releasable pool of synaptic vesicles and safeguards a fraction of them to be not immediately available for action potential-induced release. Functions also in processes other than assembly such as the regulation of specific presynaptic protein ubiquitination by interacting with SIAH1 or the regulation of presynaptic autophagy. Mediates also synapse to nucleus communication leading to reconfiguration of gene expression by associating with the transcriptional corepressor CTBP1 and by subsequently reducing the size of its pool available for nuclear import.
• Tissue Specificity: Moderately expressed in the developing cerebral cortex.
• KEGG Pathway: Insulin secretion (hsa04911)
• Reactome Pathway: Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[2]
Cryopyrin-associated periodic syndrome	DISPXXOZ	Strong	Biomarker	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[1]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[4]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[5]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[6]
Pontocerebellar hypoplasia	DISRICMU	Strong	Biomarker	[7]
Pontocerebellar hypoplasia type 3	DISR2JYJ	Strong	Autosomal recessive	[8]
Schizophrenia	DISSRV2N	Strong	Biomarker	[9]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[10]
Renal cell carcinoma	DISQZ2X8	moderate	Biomarker	[10]
Intellectual disability	DISMBNXP	Limited	Altered Expression	[11]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[12]

11 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 Protein piccolo (PCLO).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein piccolo (PCLO).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein piccolo (PCLO).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein piccolo (PCLO).	[17]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein piccolo (PCLO).	[18]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of Protein piccolo (PCLO).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein piccolo (PCLO).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Protein piccolo (PCLO).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein piccolo (PCLO).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein piccolo (PCLO).	[24]
ORG2058	DMH1M6N	Investigative	ORG2058 increases the expression of Protein piccolo (PCLO).	[25]

2 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 Protein piccolo (PCLO).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Protein piccolo (PCLO).	[23]

References

• [1] Piccolo mediates EGFR signaling and acts as a prognostic biomarker in esophageal squamous cell carcinoma.Oncogene. 2017 Jul 6;36(27):3890-3902. doi: 10.1038/onc.2017.15. Epub 2017 Mar 6.
• [2] Functional analysis of deep intronic SNP rs13438494 in intron 24 of PCLO gene.PLoS One. 2013 Oct 22;8(10):e76960. doi: 10.1371/journal.pone.0076960. eCollection 2013.
• [3] Canakinumab for the treatment of cryopyrin-associated periodic syndromes.Drugs Today (Barc). 2009 Oct;45(10):731-5.
• [4] 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.
• [5] The Piccolo Intronic Single Nucleotide Polymorphism rs13438494 Regulates Dopamine and Serotonin Uptake and Shows Associations with Dependence-Like Behavior in Genomic Association Study.Curr Mol Med. 2015;15(3):265-74. doi: 10.2174/1566524015666150330145722.
• [6] Epistatic interaction of genetic depression risk variants in the human subgenual cingulate cortex during memory encoding.Transl Psychiatry. 2014 Mar 18;4(3):e372. doi: 10.1038/tp.2014.10.
• [7] Loss of PCLO function underlies pontocerebellar hypoplasia type III. Neurology. 2015 Apr 28;84(17):1745-50. doi: 10.1212/WNL.0000000000001523. Epub 2015 Apr 1.
• [8] Piccolo and bassoon maintain synaptic vesicle clustering without directly participating in vesicle exocytosis. Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6504-9. doi: 10.1073/pnas.1002307107. Epub 2010 Mar 23.
• [9] Principal components of heritability from neurocognitive domains differ between families with schizophrenia and control subjects.Schizophr Bull. 2013 Mar;39(2):464-71. doi: 10.1093/schbul/sbr161. Epub 2012 Jan 10.
• [10] Modifiable risk factors to reduce renal cell carcinoma incidence: Insight from the PLCO trial.Urol Oncol. 2018 Jul;36(7):340.e1-340.e6. doi: 10.1016/j.urolonc.2018.04.011. Epub 2018 May 17.
• [11] Gene structure and genetic localization of the PCLO gene encoding the presynaptic active zone protein Piccolo.Int J Dev Neurosci. 2002 Jun-Aug;20(3-5):161-71. doi: 10.1016/s0736-5748(02)00046-1.
• [12] PCLO variants are nominally associated with early-onset type 2 diabetes and insulin resistance in Pima Indians.Diabetes. 2008 Nov;57(11):3156-60. doi: 10.2337/db07-1800. Epub 2008 Jul 22.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [16] 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.
• [17] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [18] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [19] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] The antiproliferative effects of progestins in T47D breast cancer cells are tempered by progestin induction of the ETS transcription factor Elf5. Mol Endocrinol. 2010 Jul;24(7):1380-92. doi: 10.1210/me.2009-0516. Epub 2010 Jun 2.