Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT403QC1)

• DOT Name: Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4 (PIN4)
• Synonyms: EC 5.2.1.8; Parvulin-14; Par14; hPar14; Parvulin-17; Par17; hPar17; Peptidyl-prolyl cis-trans isomerase Pin4; PPIase Pin4; Peptidyl-prolyl cis/trans isomerase EPVH; hEPVH; Rotamase Pin4
• Gene Name: PIN4
• Related Disease:
  Alzheimer disease
  Neoplasm
  Hyperglycemia
• UniProt ID: PIN4_HUMAN
• PDB ID: 1EQ3; 1FJD; 3UI4; 3UI5; 3UI6
• EC Number: 5.2.1.8
• Pfam ID: PF13616
• Sequence:
  MPPKGKSGSGKAGKGGAASGSDSADKKAQGPKGGGNAVKVRHILCEKHGKIMEAMEKLKS
  GMRFNEVAAQYSEDKARQGGDLGWMTRGSMVGPFQEAAFALPVSGMDKPVFTDPPVKTKF
  GYHIIMVEGRK
• Function: Isoform 1 is involved as a ribosomal RNA processing factor in ribosome biogenesis. Binds to tightly bent AT-rich stretches of double-stranded DNA; Isoform 2 binds to double-stranded DNA.
• Tissue Specificity: Isoform 2 is much more stable than isoform 1 (at protein level). Ubiquitous. Isoform 1 and isoform 2 are expressed in kidney, liver, blood vessel, brain, mammary gland, skeletal muscle, small intestine and submandibularis. Isoform 1 transcripts are much more abundant than isoform 2 in each tissue analyzed.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Hyperglycemia	DIS0BZB5	Limited	Altered Expression	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4 (PIN4) affects the response to substance of Topotecan.	[14]

9 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 Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4 (PIN4).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4 (PIN4).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4 (PIN4).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4 (PIN4).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4 (PIN4).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4 (PIN4).	[9]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4 (PIN4).	[10]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4 (PIN4).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4 (PIN4).	[13]

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 Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4 (PIN4).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4 (PIN4).	[11]

References

• [1] Insight into the structural stability of wild-type and histidine mutants in Pin1 by experimental and computational methods.Sci Rep. 2019 Jun 10;9(1):8413. doi: 10.1038/s41598-019-44926-5.
• [2] Par14 protein associates with insulin receptor substrate 1 (IRS-1), thereby enhancing insulin-induced IRS-1 phosphorylation and metabolic actions.J Biol Chem. 2013 Jul 12;288(28):20692-701. doi: 10.1074/jbc.M113.485730. Epub 2013 May 29.
• [3] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [4] 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.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] 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.
• [9] 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.
• [10] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [11] 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.
• [12] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [13] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [14] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.