Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWBA48T)

• DOT Name: Prickle-like protein 2 (PRICKLE2)
• Gene Name: PRICKLE2
• Related Disease:
  Childhood epilepsy with centrotemporal spikes
  Epilepsy
  Liver cancer
  Pervasive developmental disorder
  Precancerous condition
  Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
  Asthma
  Autism spectrum disorder
  Complex neurodevelopmental disorder
  Neuroblastoma
  Psychotic disorder
• UniProt ID: PRIC2_HUMAN
• Pfam ID: PF00412 ; PF06297
• Sequence:
  MVTVMPLEMEKTISKLMFDFQRNSTSDDDSGCALEEYAWVPPGLKPEQVHQYYSCLPEEK
  VPYVNSPGEKLRIKQLLHQLPPHDNEVRYCNSLDEEEKRELKLFSSQRKRENLGRGNVRP
  FPVTMTGAICEQCGGQINGGDIAVFASRAGHGVCWHPPCFVCTVCNELLVDLIYFYQDGK
  IYCGRHHAECLKPRCAACDEIIFADECTEAEGRHWHMKHFCCFECETVLGGQRYIMKEGR
  PYCCHCFESLYAEYCDTCAQHIGIDQGQMTYDGQHWHATETCFCCAHCKKSLLGRPFLPK
  QGQIFCSRACSAGEDPNGSDSSDSAFQNARAKESRRSAKIGKNKGKTEEPMLNQHSQLQV
  SSNRLSADVDPLSLQMDMLSLSSQTPSLNRDPIWRSREEPYHYGNKMEQNQTQSPLQLLS
  QCNIRTSYSPGGQGAGAQPEMWGKHFSNPKRSSSLAMTGHAGSFIKECREDYYPGRLRSQ
  ESYSDMSSQSFSETRGSIQVPKYEEEEEEEGGLSTQQCRTRHPISSLKYTEDMTPTEQTP
  RGSMESLALSNATGLSADGGAKRQEHLSRFSMPDLSKDSGMNVSEKLSNMGTLNSSMQFR
  SAESVRSLLSAQQYQEMEGNLHQLSNPIGYRDLQSHGRMHQSFDFDGGMAGSKLPGQEGV
  RIQPMSERTRRRATSRDDNRRFRPHRSRRSRRSRSDNALHLASEREAISRLKDRPPLRAR
  EDYDQFMRQRSFQESMGHGSRRDLYGQCPRTVSDLALQNAFGDRWGPYFAEYDWCSTCSS
  SSESDNEGYFLGEPIPQPARLRYVTSDELLHKYSSYGLPKSSTLGGRGQLHSRKRQKSKN
  CIIS
• Tissue Specificity: Expressed in brain, eye and testis. Additionally in fetal brain, adult cartilage, pancreatic islet, gastric cancer and uterus tumors.
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Childhood epilepsy with centrotemporal spikes	DISKT2L5	Strong	CausalMutation	[1]
Epilepsy	DISBB28L	Strong	Genetic Variation	[2]
Liver cancer	DISDE4BI	Strong	Biomarker	[3]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[2]
Precancerous condition	DISV06FL	Strong	Biomarker	[3]
Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	DISC52SS	Strong	CausalMutation	[4]
Asthma	DISW9QNS	moderate	Genetic Variation	[5]
Autism spectrum disorder	DISXK8NV	Limited	Genetic Variation	[2]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal dominant	[6]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[7]
Psychotic disorder	DIS4UQOT	Limited	Biomarker	[8]

12 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 2 (PRICKLE2).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Prickle-like protein 2 (PRICKLE2).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Prickle-like protein 2 (PRICKLE2).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Prickle-like protein 2 (PRICKLE2).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Prickle-like protein 2 (PRICKLE2).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Prickle-like protein 2 (PRICKLE2).	[14]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Prickle-like protein 2 (PRICKLE2).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Prickle-like protein 2 (PRICKLE2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Prickle-like protein 2 (PRICKLE2).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Prickle-like protein 2 (PRICKLE2).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Prickle-like protein 2 (PRICKLE2).	[22]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of Prickle-like protein 2 (PRICKLE2).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Selenium	DM25CGV	Approved	Selenium decreases the methylation of Prickle-like protein 2 (PRICKLE2).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Prickle-like protein 2 (PRICKLE2).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Prickle-like protein 2 (PRICKLE2).	[19]

References

• [1] Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy.Eur J Hum Genet. 2018 Feb;26(2):258-264. doi: 10.1038/s41431-017-0034-x. Epub 2018 Jan 22.
• [2] Vangl2 interaction plays a role in the proteasomal degradation of Prickle2.Sci Rep. 2019 Feb 27;9(1):2912. doi: 10.1038/s41598-019-39642-z.
• [3] Multiple genes exhibit phenobarbital-induced constitutive active/androstane receptor-mediated DNA methylation changes during liver tumorigenesis and in liver tumors.Toxicol Sci. 2009 Apr;108(2):273-89. doi: 10.1093/toxsci/kfp031. Epub 2009 Feb 20.
• [4] Mutations in prickle orthologs cause seizures in flies, mice, and humans.Am J Hum Genet. 2011 Feb 11;88(2):138-49. doi: 10.1016/j.ajhg.2010.12.012. Epub 2011 Feb 3.
• [5] Genome-Wide Association Study Identifies Novel Loci Associated With Diisocyanate-Induced Occupational Asthma.Toxicol Sci. 2015 Jul;146(1):192-201. doi: 10.1093/toxsci/kfv084. Epub 2015 Apr 26.
• [6] 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.
• [7] Role of Prickle1 and Prickle2 in neurite outgrowth in murine neuroblastoma cells.Methods Mol Biol. 2012;839:173-85. doi: 10.1007/978-1-61779-510-7_14.
• [8] A novel relationship for schizophrenia, bipolar and major depressive disorder Part 3: Evidence from chromosome 3 high density association screen.J Comp Neurol. 2018 Jan 1;526(1):59-79. doi: 10.1002/cne.24311. Epub 2017 Oct 16.
• [9] 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.
• [10] 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.
• [11] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] 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.
• [14] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [15] Epigenetic assessment of environmental chemicals detected in maternal peripheral and cord blood samples. J Reprod Dev. 2011 Sep;57(4):507-17. doi: 10.1262/jrd.11-034a. Epub 2011 May 23.
• [16] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [21] 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.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.