Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9HHEM9)

• DOT Name: Prickle-like protein 1 (PRICKLE1)
• Synonyms: REST/NRSF-interacting LIM domain protein 1
• Gene Name: PRICKLE1
• Related Disease:
  Advanced cancer
  Cardiac disease
  Cerebellar ataxia
  Corpus callosum, agenesis of
  Epilepsy, progressive myoclonic, 1B
  Graves disease
  Hepatocellular carcinoma
  Neural tube defect
  Neuroblastoma
  Pervasive developmental disorder
  Primary biliary cholangitis
  Temporal lobe epilepsy
  Triple negative breast cancer
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Neoplasm
  Unverricht-Lundborg syndrome
  Epilepsy
  Autism spectrum disorder
  Pneumocystis pneumonia
  Progressive myoclonus epilepsy
• UniProt ID: PRIC1_HUMAN
• Pfam ID: PF00412 ; PF06297
• Sequence:
  MPLEMEPKMSKLAFGCQRSSTSDDDSGCALEEYAWVPPGLRPEQIQLYFACLPEEKVPYV
  NSPGEKHRIKQLLYQLPPHDNEVRYCQSLSEEEKKELQVFSAQRKKEALGRGTIKLLSRA
  VMHAVCEQCGLKINGGEVAVFASRAGPGVCWHPSCFVCFTCNELLVDLIYFYQDGKIHCG
  RHHAELLKPRCSACDEIIFADECTEAEGRHWHMKHFCCLECETVLGGQRYIMKDGRPFCC
  GCFESLYAEYCETCGEHIGVDHAQMTYDGQHWHATEACFSCAQCKASLLGCPFLPKQGQI
  YCSKTCSLGEDVHASDSSDSAFQSARSRDSRRSVRMGKSSRSADQCRQSLLLSPALNYKF
  PGLSGNADDTLSRKLDDLSLSRQGTSFASEEFWKGRVEQETPEDPEEWADHEDYMTQLLL
  KFGDKSLFQPQPNEMDIRASEHWISDNMVKSKTELKQNNQSLASKKYQSDMYWAQSQDGL
  GDSAYGSHPGPASSRRLQELELDHGASGYNHDETQWYEDSLECLSDLKPEQSVRDSMDSL
  ALSNITGASVDGENKPRPSLYSLQNFEEMETEDCEKMSNMGTLNSSMLHRSAESLKSLSS
  ELCPEKILPEEKPVHLPVLRRSKSQSRPQQVKFSDDVIDNGNYDIEIRQPPMSERTRRRV
  YNFEERGSRSHHHRRRRSRKSRSDNALNLVTERKYSPKDRLRLYTPDNYEKFIQNKSARE
  IQAYIQNADLYGQYAHATSDYGLQNPGMNRFLGLYGEDDDSWCSSSSSSSDSEEEGYFLG
  QPIPQPRPQRFAYYTDDLSSPPSALPTPQFGQRTTKSKKKKGHKGKNCIIS
• Function: Involved in the planar cell polarity pathway that controls convergent extension during gastrulation and neural tube closure. Convergent extension is a complex morphogenetic process during which cells elongate, move mediolaterally, and intercalate between neighboring cells, leading to convergence toward the mediolateral axis and extension along the anteroposterior axis. Necessary for nuclear localization of REST. May serve as nuclear receptor.
• Tissue Specificity: Expressed at highest levels in placenta and at lower levels in lung, liver, kidney and pancreas. Expressed in thalamus, hippocampus, cerebral cortex, and cerebellum (in neurons rather than glia).
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)
• Reactome Pathway: Asymmetric localization of PCP proteins (R-HSA-4608870)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Cardiac disease	DISVO1I5	Strong	Genetic Variation	[2]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[2]
Corpus callosum, agenesis of	DISO9P40	Strong	Genetic Variation	[3]
Epilepsy, progressive myoclonic, 1B	DISZDF43	Strong	Autosomal recessive	[4]
Graves disease	DISU4KOQ	Strong	Genetic Variation	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Neural tube defect	DIS5J95E	Strong	Biomarker	[7]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[8]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[9]
Primary biliary cholangitis	DIS43E0O	Strong	Genetic Variation	[10]
Temporal lobe epilepsy	DISNOPXX	Strong	Therapeutic	[11]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[12]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	moderate	Biomarker	[13]
Liver cancer	DISDE4BI	moderate	Biomarker	[13]
Neoplasm	DISZKGEW	moderate	Altered Expression	[13]
Unverricht-Lundborg syndrome	DISG4WLX	Supportive	Autosomal recessive	[4]
Epilepsy	DISBB28L	Disputed	Autosomal dominant	[14]
Autism spectrum disorder	DISXK8NV	Limited	Genetic Variation	[9]
Pneumocystis pneumonia	DISFSOM3	Limited	Biomarker	[15]
Progressive myoclonus epilepsy	DISAMCNS	Limited	Autosomal recessive	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Prickle-like protein 1 (PRICKLE1).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Prickle-like protein 1 (PRICKLE1).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Prickle-like protein 1 (PRICKLE1).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Prickle-like protein 1 (PRICKLE1).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Prickle-like protein 1 (PRICKLE1).	[20]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Prickle-like protein 1 (PRICKLE1).	[21]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Prickle-like protein 1 (PRICKLE1).	[22]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Prickle-like protein 1 (PRICKLE1).	[23]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Prickle-like protein 1 (PRICKLE1).	[24]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Prickle-like protein 1 (PRICKLE1).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Prickle-like protein 1 (PRICKLE1).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Prickle-like protein 1 (PRICKLE1).	[27]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Prickle-like protein 1 (PRICKLE1).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Prickle-like protein 1 (PRICKLE1).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Prickle-like protein 1 (PRICKLE1).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Prickle-like protein 1 (PRICKLE1).	[30]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Prickle-like protein 1 (PRICKLE1).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Prickle-like protein 1 (PRICKLE1).	[31]

References

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• [2] Sudden unexpected death with rare compound heterozygous variants in PRICKLE1.Neurogenetics. 2019 Mar;20(1):39-43. doi: 10.1007/s10048-018-0562-8. Epub 2018 Dec 18.
• [3] A de novo mutation in PRICKLE1 in fetal agenesis of the corpus callosum and polymicrogyria.J Neurogenet. 2015;29(4):174-7. doi: 10.3109/01677063.2015.1088847. Epub 2016 Jan 4.
• [4] A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome. Am J Hum Genet. 2008 Nov;83(5):572-81. doi: 10.1016/j.ajhg.2008.10.003. Epub 2008 Oct 30.
• [5] Seven newly identified loci for autoimmune thyroid disease.Hum Mol Genet. 2012 Dec 1;21(23):5202-8. doi: 10.1093/hmg/dds357. Epub 2012 Aug 24.
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• [8] Planar cell polarity gene expression correlates with tumor cell viability and prognostic outcome in neuroblastoma.BMC Cancer. 2016 Mar 31;16:259. doi: 10.1186/s12885-016-2293-2.
• [9] A de novo mutation in PRICKLE1 associated with myoclonic epilepsy and autism spectrum disorder.J Neurogenet. 2018 Dec;32(4):313-315. doi: 10.1080/01677063.2018.1473862. Epub 2018 May 23.
• [10] Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis.Nat Genet. 2011 Mar 13;43(4):329-32. doi: 10.1038/ng.789.
• [11] Neuron-restrictive silencer factor-mediated hyperpolarization-activated cyclic nucleotide gated channelopathy in experimental temporal lobe epilepsy.Ann Neurol. 2011 Sep;70(3):454-64. doi: 10.1002/ana.22479.
• [12] ECT2 associated to PRICKLE1 are poor-prognosis markers in triple-negative breast cancer.Br J Cancer. 2019 Apr;120(9):931-940. doi: 10.1038/s41416-019-0448-z. Epub 2019 Apr 11.
• [13] Prickle-1 negatively regulates Wnt/beta-catenin pathway by promoting Dishevelled ubiquitination/degradation in liver cancer.Gastroenterology. 2006 Oct;131(4):1218-27. doi: 10.1053/j.gastro.2006.07.020. Epub 2006 Jul 24.
• [14] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [15] Prickle1 regulates neurite outgrowth of apical spiral ganglion neurons but not hair cell polarity in the murine cochlea.PLoS One. 2017 Aug 24;12(8):e0183773. doi: 10.1371/journal.pone.0183773. eCollection 2017.
• [16] 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.
• [17] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [18] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [19] 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.
• [20] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [21] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [22] 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.
• [23] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [24] 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.
• [25] 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.
• [26] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [27] 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.
• [28] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [29] Genome-wide gene expression profiling of low-dose, long-term exposure of human osteosarcoma cells to bisphenol A and its analogs bisphenols AF and S. Toxicol In Vitro. 2015 Aug;29(5):1060-9.
• [30] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [31] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [32] 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.