Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ3UHWQ)

• DOT Name: Exopolyphosphatase PRUNE1 (PRUNE1)
• Synonyms: EC 3.6.1.1; Drosophila-related expressed sequence 17; DRES-17; DRES17; HTcD37; Protein prune homolog 1; hPrune
• Gene Name: PRUNE1
• Related Disease:
  Neuroblastoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Gastric cancer
  Isolated congenital microcephaly
  Medulloblastoma
  Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies
  Metastatic malignant neoplasm
  Leiomyosarcoma
  Liposarcoma
  Malignant soft tissue neoplasm
  Neurodevelopmental disorder
  Sarcoma
• UniProt ID: PRUN1_HUMAN
• EC Number: 3.6.1.1
• Pfam ID: PF01368 ; PF02833
• Sequence:
  MEDYLQGCRAALQESRPLHVVLGNEACDLDSTVSALALAFYLAKTTEAEEVFVPVLNIKR
  SELPLRGDIVFFLQKVHIPESILIFRDEIDLHALYQAGQLTLILVDHHILSKSDTALEEA
  VAEVLDHRPIEPKHCPPCHVSVELVGSCATLVTERILQGAPEILDRQTAALLHGTIILDC
  VNMDLKIGKATPKDSKYVEKLEALFPDLPKRNDIFDSLQKAKFDVSGLTTEQMLRKDQKT
  IYRQGVKVAISAIYMDLEAFLQRSNLLADLHAFCQAHSYDVLVAMTIFFNTHNEPVRQLA
  IFCPHVALQTTICEVLERSHSPPLKLTPASSTHPNLHAYLQGNTQVSRKKLLPLLQEALS
  AYFDSMKIPSGQPETADVSREQVDKELDRASNSLISGLSQDEEDPPLPPTPMNSLVDECP
  LDQGLPKLSAEAVFEKCSQISLSQSTTASLSKK
• Function: Phosphodiesterase (PDE) that has higher activity toward cAMP than cGMP, as substrate. Plays a role in cell proliferation, migration and differentiation, and acts as a negative regulator of NME1. Plays a role in the regulation of neurogenesis. Involved in the regulation of microtubule polymerization.
• Tissue Specificity: Ubiquitously expressed. Seems to be overexpressed in aggressive sarcoma subtypes, such as leiomyosarcomas and malignant fibrous histiocytomas (MFH) as well as in the less malignant liposarcomas.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neuroblastoma	DISVZBI4	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[5]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[6]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[7]
Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies	DISIWKCF	Strong	Autosomal recessive	[8]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[9]
Leiomyosarcoma	DIS6COXM	Limited	Biomarker	[10]
Liposarcoma	DIS8IZVM	Limited	Biomarker	[10]
Malignant soft tissue neoplasm	DISTC6NO	Limited	Biomarker	[10]
Neurodevelopmental disorder	DIS372XH	Limited	Genetic Variation	[6]
Sarcoma	DISZDG3U	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Exopolyphosphatase PRUNE1 (PRUNE1).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Exopolyphosphatase PRUNE1 (PRUNE1).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Exopolyphosphatase PRUNE1 (PRUNE1).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of Exopolyphosphatase PRUNE1 (PRUNE1).	[14]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Exopolyphosphatase PRUNE1 (PRUNE1).	[15]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Exopolyphosphatase PRUNE1 (PRUNE1).	[16]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Exopolyphosphatase PRUNE1 (PRUNE1).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Exopolyphosphatase PRUNE1 (PRUNE1).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Exopolyphosphatase PRUNE1 (PRUNE1).	[19]

References

• [1] Neuroblastoma tumorigenesis is regulated through the Nm23-H1/h-Prune C-terminal interaction.Sci Rep. 2013;3:1351. doi: 10.1038/srep01351.
• [2] A competitive cell-permeable peptide impairs Nme-1 (NDPK-A) and Prune-1 interaction: therapeutic applications in cancer.Lab Invest. 2018 May;98(5):571-581. doi: 10.1038/s41374-017-0011-6. Epub 2018 Feb 15.
• [3] Phosphorylation of nm23-H1 by CKI induces its complex formation with h-prune and promotes cell motility.Oncogene. 2008 Mar 20;27(13):1853-64. doi: 10.1038/sj.onc.1210822. Epub 2007 Oct 1.
• [4] Overexpression of h-prune in breast cancer is correlated with advanced disease status.Clin Cancer Res. 2005 Jan 1;11(1):199-205.
• [5] Understanding h-prune biology in the fight against cancer.Clin Exp Metastasis. 2007;24(8):637-45. doi: 10.1007/s10585-007-9109-3. Epub 2007 Oct 19.
• [6] A homozygous canonical splice acceptor site mutation in PRUNE1 is responsible for a rare childhood neurodegenerative disease in Manitoba Cree families.Am J Med Genet A. 2019 Feb;179(2):206-218. doi: 10.1002/ajmg.a.60690. Epub 2018 Dec 17.
• [7] Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF--OTX2-SNAIL via PTEN inhibition.Brain. 2018 May 1;141(5):1300-1319. doi: 10.1093/brain/awy039.
• [8] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [9] Integrative analysis of h-prune as a potential therapeutic target for hepatocellular carcinoma.EBioMedicine. 2019 Mar;41:310-319. doi: 10.1016/j.ebiom.2019.01.001. Epub 2019 Jan 18.
• [10] Amplification and overexpression of PRUNE in human sarcomas and breast carcinomas-a possible mechanism for altering the nm23-H1 activity.Oncogene. 2001 Oct 18;20(47):6881-90. doi: 10.1038/sj.onc.1204874.
• [11] 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.
• [12] 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.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] 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.
• [15] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [16] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [17] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [18] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.