Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPJL6ML)

• DOT Name: Peptidase inhibitor 15 (PI15)
• Synonyms: PI-15; 25 kDa trypsin inhibitor; p25TI; Cysteine-rich secretory protein 8; CRISP-8; SugarCrisp
• Gene Name: PI15
• Related Disease:
  Adult glioblastoma
  Bladder cancer
  Cholangiocarcinoma
  Congenital contractural arachnodactyly
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Neuroblastoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Idiopathic interstitial pneumonia
• UniProt ID: PI15_HUMAN
• Pfam ID: PF00188
• Sequence:
  MIAISAVSSALLFSLLCEASTVVLLNSTDSSPPTNNFTDIEAALKAQLDSADIPKARRKR
  YISQNDMIAILDYHNQVRGKVFPPAANMEYMVWDENLAKSAEAWAATCIWDHGPSYLLRF
  LGQNLSVRTGRYRSILQLVKPWYDEVKDYAFPYPQDCNPRCPMRCFGPMCTHYTQMVWAT
  SNRIGCAIHTCQNMNVWGSVWRRAVYLVCNYAPKGNWIGEAPYKVGVPCSSCPPSYGGSC
  TDNLCFPGVTSNYLYWFK
• Function: Serine protease inhibitor which displays weak inhibitory activity against trypsin. May play a role in facial patterning during embryonic development.
• Tissue Specificity: Weakly expressed. Expressed at low level in prostate, mammary gland, salivary gland and thyroid gland.

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Bladder cancer	DISUHNM0	Strong	Biomarker	[2]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[3]
Congenital contractural arachnodactyly	DISOM1K7	Strong	Biomarker	[3]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[3]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[1]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[2]
Idiopathic interstitial pneumonia	DISH7LPY	Limited	Biomarker	[4]

6 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 Peptidase inhibitor 15 (PI15).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Peptidase inhibitor 15 (PI15).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Peptidase inhibitor 15 (PI15).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Peptidase inhibitor 15 (PI15).	[8]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Peptidase inhibitor 15 (PI15).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Peptidase inhibitor 15 (PI15).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Peptidase inhibitor 15 (PI15).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Peptidase inhibitor 15 (PI15).	[11]

References

• [1] cDNA cloning of a novel trypsin inhibitor with similarity to pathogenesis-related proteins, and its frequent expression in human brain cancer cells.Biochim Biophys Acta. 1998 Jan 21;1395(2):202-8. doi: 10.1016/s0167-4781(97)00149-8.
• [2] Dysregulated genes targeted by microRNAs and metabolic pathways in bladder cancer revealed by bioinformatics methods.Oncol Lett. 2018 Jun;15(6):9617-9624. doi: 10.3892/ol.2018.8602. Epub 2018 Apr 27.
• [3] Peptidase inhibitor 15 as a novel blood diagnostic marker for cholangiocarcinoma.EBioMedicine. 2019 Feb;40:422-431. doi: 10.1016/j.ebiom.2018.12.063. Epub 2019 Jan 9.
• [4] Relationship between gene expression and lung function in Idiopathic Interstitial Pneumonias.BMC Genomics. 2015 Oct 26;16:869. doi: 10.1186/s12864-015-2102-3.
• [5] 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.
• [6] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] 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.
• [8] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [9] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [10] 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.
• [11] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [12] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.