Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDS5WAU)

• DOT Name: Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1)
• Synonyms: EC 5.2.1.8; Peptidyl-prolyl cis-trans isomerase Pin1; PPIase Pin1; Rotamase Pin1
• Gene Name: PIN1
• UniProt ID: PIN1_HUMAN
• PDB ID: 1F8A ; 1I6C ; 1I8G ; 1I8H ; 1NMV ; 1NMW ; 1PIN ; 1ZCN ; 2F21 ; 2ITK ; 2KBU ; 2KCF ; 2LB3 ; 2M8I ; 2M8J ; 2M9E ; 2M9F ; 2M9I ; 2M9J ; 2N1O ; 2Q5A ; 2RUC ; 2RUD ; 2RUQ ; 2RUR ; 2XP3 ; 2XP4 ; 2XP5 ; 2XP6 ; 2XP7 ; 2XP8 ; 2XP9 ; 2XPA ; 2XPB ; 2ZQS ; 2ZQT ; 2ZQU ; 2ZQV ; 2ZR4 ; 2ZR5 ; 2ZR6 ; 3I6C ; 3IK8 ; 3IKD ; 3IKG ; 3JYJ ; 3KAB ; 3KAC ; 3KAD ; 3KAF ; 3KAG ; 3KAH ; 3KAI ; 3KCE ; 3NTP ; 3ODK ; 3OOB ; 3TC5 ; 3TCZ ; 3TDB ; 3WH0 ; 4GWT ; 4GWV ; 4QIB ; 4TNS ; 4TYO ; 4U84 ; 4U85 ; 4U86 ; 5B3W ; 5B3X ; 5B3Y ; 5B3Z ; 5BMY ; 5GPH ; 5UY9 ; 5VTI ; 5VTJ ; 5VTK ; 6DUN ; 6O33 ; 6O34 ; 6SVC ; 6SVE ; 6SVH ; 6VAJ ; 7AOG ; 7AXN ; 7AYF ; 7AZ1 ; 7AZ2 ; 7BDP ; 7BDT ; 7BDY ; 7BFW ; 7BG3 ; 7BGQ ; 7BGR ; 7BGV ; 7BGW ; 7EFJ ; 7EFX ; 7EKV ; 7F0M ; 7NIF ; 7NIG ; 7NJ6 ; 7NJ8 ; 7NJA ; 7NRK ; 7NRL ; 7OQ9 ; 7OQA ; 7SA5 ; 7SUQ ; 7SUR ; 8C2G ; 8C3C
• EC Number: 5.2.1.8
• Pfam ID: PF00639 ; PF00397
• Sequence:
  MADEEKLPPGWEKRMSRSSGRVYYFNHITNASQWERPSGNSSSGGKNGQGEPARVRCSHL
  LVKHSQSRRPSSWRQEKITRTKEEALELINGYIQKIKSGEEDFESLASQFSDCSSAKARG
  DLGAFSRGQMQKPFEDASFALRTGEMSGPVFTDSGIHIILRTE
• Function: Peptidyl-prolyl cis/trans isomerase (PPIase) that binds to and isomerizes specific phosphorylated Ser/Thr-Pro (pSer/Thr-Pro) motifs. By inducing conformational changes in a subset of phosphorylated proteins, acts as a molecular switch in multiple cellular processes. Displays a preference for acidic residues located N-terminally to the proline bond to be isomerized. Regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity. Down-regulates kinase activity of BTK. Can transactivate multiple oncogenes and induce centrosome amplification, chromosome instability and cell transformation. Required for the efficient dephosphorylation and recycling of RAF1 after mitogen activation. Binds and targets PML and BCL6 for degradation in a phosphorylation-dependent manner. Acts as a regulator of JNK cascade by binding to phosphorylated FBXW7, disrupting FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation: degradation of FBXW7 leads to subsequent stabilization of JUN. May facilitate the ubiquitination and proteasomal degradation of RBBP8/CtIP through CUL3/KLHL15 E3 ubiquitin-protein ligase complex, hence favors DNA double-strand repair through error-prone non-homologous end joining (NHEJ) over error-free, RBBP8-mediated homologous recombination (HR). Upon IL33-induced lung inflammation, catalyzes cis-trans isomerization of phosphorylated IRAK3/IRAK-M, inducing IRAK3 stabilization, nuclear translocation and expression of pro-inflammatory genes in dendritic cells.
• Tissue Specificity: Expressed in immune cells in the lung (at protein level) . The phosphorylated form at Ser-71 is expressed in normal breast tissue cells but not in breast cancer cells.
• KEGG Pathway:
  Viral life cycle - HIV-1 (hsa03250)
  RIG-I-like receptor sig.ling pathway (hsa04622)
• Reactome Pathway:
  RHO GTPases Activate NADPH Oxidases (R-HSA-5668599)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  PI5P Regulates TP53 Acetylation (R-HSA-6811555)
  Negative regulators of DDX58/IFIH1 signaling (R-HSA-936440)
  ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) affects the response to substance of Methotrexate.	[13]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) increases the response to substance of 4-hydroxy-2-nonenal.	[14]

13 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 1 (PIN1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1).	[8]
LY294002	DMY1AFS	Phase 1	LY294002 decreases the expression of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1).	[10]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1).	[11]
Syringic Acid	DM802V7	Investigative	Syringic Acid decreases the expression of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1).	[12]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Inhibition of angiogenesis by quercetin in tamoxifen-resistant breast cancer cells. Food Chem Toxicol. 2010 Nov;48(11):3227-34. doi: 10.1016/j.fct.2010.08.028. Epub 2010 Sep 4.
• [7] 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.
• [8] Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells. Nat Commun. 2018 Aug 9;9(1):3069. doi: 10.1038/s41467-018-05402-2.
• [9] 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.
• [10] 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.
• [11] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.
• [12] Syringic acid regulates suppression of the STAT3/JNK/AKT pathway via inhibition of human ovarian teratoma cancer cell?(PA-1) growth-in vitro study. J Biochem Mol Toxicol. 2021 Jun;35(6):1-9. doi: 10.1002/jbt.22776. Epub 2021 Mar 23.
• [13] 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.
• [14] Peptidyl-prolyl cis/trans-isomerase A1 (Pin1) is a target for modification by lipid electrophiles. Chem Res Toxicol. 2013 Feb 18;26(2):270-9. doi: 10.1021/tx300449g. Epub 2012 Dec 24.