Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT47MTC3)

• DOT Name: Elafin (PI3)
• Synonyms: Elastase-specific inhibitor; ESI; Peptidase inhibitor 3; PI-3; Protease inhibitor WAP3; Skin-derived antileukoproteinase; SKALP; WAP four-disulfide core domain protein 14
• Gene Name: PI3
• Related Disease:
  Acute graft versus host disease
  Coeliac disease
  Ductal breast carcinoma in situ
  Myocardial infarction
  Acute coronary syndrome
  Adult respiratory distress syndrome
  Atopic dermatitis
  Bacterial infection
  Bacterial vaginosis
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Chronic graft versus host disease
  Colitis
  Colorectal carcinoma
  Colorectal neoplasm
  Cystic fibrosis
  Epithelial ovarian cancer
  Gingivitis
  Glioblastoma multiforme
  HIV infectious disease
  Knee osteoarthritis
  Melanoma
  Neoplasm
  Osteoarthritis
  Ovarian cancer
  Ovarian neoplasm
  Pneumonia
  Pneumonitis
  Psoriasis
  Retinoblastoma
  Rheumatoid arthritis
  Skin disease
  Vascular disease
  Chronic obstructive pulmonary disease
  Invasive breast carcinoma
  Periodontitis
  Pulmonary disease
  Ulcerative colitis
  Asthma
  Contact dermatitis
  Crohn disease
  Graft-versus-host disease
  Inflammatory bowel disease
  Systemic sclerosis
  Type-1 diabetes
• UniProt ID: ELAF_HUMAN
• PDB ID: 1FLE; 2REL; 6ATU
• Pfam ID: PF10511 ; PF00095
• Sequence:
  MRASSFLIVVVFLIAGTLVLEAAVTGVPVKGQDTVKGRVPFNGQDPVKGQVSVKGQDKVK
  AQEPVKGPVSTKPGSCPIILIRCAMLNPPNRCLKDTDCPGIKKCCEGSCGMACFVPQ
• Function: Neutrophil and pancreatic elastase-specific inhibitor of skin. It may prevent elastase-mediated tissue proteolysis. Has been shown to inhibit the alpha-4-beta-2/CHRNA2-CHRNB2 nicotinic acetylcholine receptor and to produce a weak inhibition on Kv11.1/KCNH2/ERG1 and on the transient receptor potential cation channel subfamily V member 1 (TRPV1).
• Reactome Pathway:
  Formation of the cornified envelope (R-HSA-6809371)
  Antimicrobial peptides (R-HSA-6803157)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute graft versus host disease	DIS8KLVM	Definitive	Biomarker	[1]
Coeliac disease	DISIY60C	Definitive	Biomarker	[2]
Ductal breast carcinoma in situ	DISLCJY7	Definitive	Altered Expression	[3]
Myocardial infarction	DIS655KI	Definitive	Biomarker	[4]
Acute coronary syndrome	DIS7DYEW	Strong	Biomarker	[5]
Adult respiratory distress syndrome	DISIJV47	Strong	Biomarker	[6]
Atopic dermatitis	DISTCP41	Strong	Biomarker	[7]
Bacterial infection	DIS5QJ9S	Strong	Altered Expression	[8]
Bacterial vaginosis	DISK2MZ2	Strong	Biomarker	[9]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[10]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[10]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[11]
Carcinoma	DISH9F1N	Strong	Altered Expression	[12]
Chronic graft versus host disease	DIS1MM9J	Strong	Biomarker	[13]
Colitis	DISAF7DD	Strong	Altered Expression	[14]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[15]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[15]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[16]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[11]
Gingivitis	DISC8RMX	Strong	Altered Expression	[17]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[18]
HIV infectious disease	DISO97HC	Strong	Altered Expression	[19]
Knee osteoarthritis	DISLSNBJ	Strong	Biomarker	[20]
Melanoma	DIS1RRCY	Strong	Altered Expression	[21]
Neoplasm	DISZKGEW	Strong	Altered Expression	[11]
Osteoarthritis	DIS05URM	Strong	Biomarker	[20]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[11]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[22]
Pneumonia	DIS8EF3M	Strong	Altered Expression	[16]
Pneumonitis	DIS88E0K	Strong	Altered Expression	[16]
Psoriasis	DIS59VMN	Strong	Altered Expression	[23]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[24]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[25]
Skin disease	DISDW8R6	Strong	Biomarker	[2]
Vascular disease	DISVS67S	Strong	Altered Expression	[26]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[27]
Invasive breast carcinoma	DISANYTW	moderate	Altered Expression	[3]
Periodontitis	DISI9JOI	moderate	Biomarker	[17]
Pulmonary disease	DIS6060I	moderate	Biomarker	[16]
Ulcerative colitis	DIS8K27O	moderate	Altered Expression	[28]
Asthma	DISW9QNS	Limited	Biomarker	[29]
Contact dermatitis	DISQ3AU0	Limited	Biomarker	[30]
Crohn disease	DIS2C5Q8	Limited	Altered Expression	[28]
Graft-versus-host disease	DIS0QADF	Limited	Biomarker	[1]
Inflammatory bowel disease	DISGN23E	Limited	Altered Expression	[28]
Systemic sclerosis	DISF44L6	Limited	Altered Expression	[26]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Elafin (PI3) affects the response to substance of Methotrexate.	[43]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Elafin (PI3).	[32]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Elafin (PI3).	[33]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Elafin (PI3).	[34]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Elafin (PI3).	[35]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Elafin (PI3).	[36]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Elafin (PI3).	[37]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Elafin (PI3).	[38]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Elafin (PI3).	[39]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Elafin (PI3).	[40]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Elafin (PI3).	[42]

1 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 increases the methylation of Elafin (PI3).	[41]

References

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• [2] Expression of Elafin in Dermatitis Herpetiformis.Am J Dermatopathol. 2018 Jan;40(1):1-6. doi: 10.1097/DAD.0000000000000915.
• [3] Elafin is downregulated during breast and ovarian tumorigenesis but its residual expression predicts recurrence.Breast Cancer Res. 2014;16(6):3417. doi: 10.1186/s13058-014-0497-4.
• [4] Elafin-overexpressing mice have improved cardiac function after myocardial infarction.Am J Physiol Heart Circ Physiol. 2004 Jul;287(1):H286-92. doi: 10.1152/ajpheart.00479.2002. Epub 2003 Dec 23.
• [5] Expression of tissue transglutaminase and elafin in human coronary artery: implication for plaque instability.Atherosclerosis. 2002 Jan;160(1):31-9. doi: 10.1016/s0021-9150(01)00542-1.
• [6] Plasma Neutrophil Elastase and Elafin as Prognostic Biomarker for Acute Respiratory Distress Syndrome: A Multicenter Survival and Longitudinal Prospective Observation Study.Shock. 2017 Aug;48(2):168-174. doi: 10.1097/SHK.0000000000000845.
• [7] The blood proteomic signature of early-onset pediatric atopic dermatitis shows systemic inflammation and is distinct from adult long-standing disease.J Am Acad Dermatol. 2019 Aug;81(2):510-519. doi: 10.1016/j.jaad.2019.04.036. Epub 2019 Apr 19.
• [8] Adenoviral augmentation of elafin protects the lung against acute injury mediated by activated neutrophils and bacterial infection.J Immunol. 2001 Aug 1;167(3):1778-86. doi: 10.4049/jimmunol.167.3.1778.
• [9] Anti-inflammatory Elafin in human fetal membranes.J Perinat Med. 2017 Feb 1;45(2):237-244. doi: 10.1515/jpm-2016-0139.
• [10] The serine protease inhibitor elafin maintains normal growth control by opposing the mitogenic effects of neutrophil elastase.Oncogene. 2015 Jul;34(27):3556-67. doi: 10.1038/onc.2014.284. Epub 2014 Sep 8.
• [11] Elafin drives poor outcome in high-grade serous ovarian cancers and basal-like breast tumors.Oncogene. 2015 Jan 15;34(3):373-83. doi: 10.1038/onc.2013.562. Epub 2014 Jan 27.
• [12] Differential expression of elafin in human normal mammary epithelial cells and carcinomas is regulated at the transcriptional level.Cancer Res. 1995 Jun 15;55(12):2537-41.
• [13] B-cell activating factor (BAFF) plasma level at the time of chronic GvHD diagnosis is a potential predictor of non-relapse mortality.Bone Marrow Transplant. 2017 Jul;52(7):1010-1015. doi: 10.1038/bmt.2017.73. Epub 2017 May 8.
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• [15] High Expression and Clinical Significance of Elafin in Colorectal Cancer.Gastroenterol Res Pract. 2019 Jun 9;2019:4946824. doi: 10.1155/2019/4946824. eCollection 2019.
• [16] A functional variant of elafin with improved anti-inflammatory activity for pulmonary inflammation.Mol Ther. 2015 Jan;23(1):24-31. doi: 10.1038/mt.2014.162. Epub 2014 Sep 5.
• [17] Alarm anti-protease trappin-2 negatively correlates with proinflammatory cytokines in patients with periodontitis.J Periodontol. 2018 Jan;89(1):58-66. doi: 10.1902/jop.2017.170245.
• [18] Experimental anti-angiogenesis causes upregulation of genes associated with poor survival in glioblastoma.Int J Cancer. 2008 May 15;122(10):2187-98. doi: 10.1002/ijc.23313.
• [19] New approaches to making the microenvironment of the female reproductive tract hostile to HIV.Am J Reprod Immunol. 2011 Mar;65(3):334-43. doi: 10.1111/j.1600-0897.2010.00949.x. Epub 2011 Jan 12.
• [20] The serine protease inhibitor trappin-2 is present in cartilage and synovial fluid in osteoarthritis.J Rheumatol. 2006 Feb;33(2):318-25.
• [21] Epigenetic regulation of the transcription factor Foxa2 directs differential elafin expression in melanocytes and melanoma cells.Biochem Biophys Res Commun. 2011 Apr 29;408(1):160-6. doi: 10.1016/j.bbrc.2011.04.001. Epub 2011 Apr 3.
• [22] Overexpression of elafin in ovarian carcinoma is driven by genomic gains and activation of the nuclear factor kappaB pathway and is associated with poor overall survival.Neoplasia. 2010 Feb;12(2):161-72. doi: 10.1593/neo.91542.
• [23] Serum elafin as a potential inflammatory marker in psoriasis.Int J Dermatol. 2019 Feb;58(2):205-209. doi: 10.1111/ijd.14217. Epub 2018 Sep 9.
• [24] The neutrophil elastase inhibitor elafin triggers rb-mediated growth arrest and caspase-dependent apoptosis in breast cancer.Cancer Res. 2010 Sep 15;70(18):7125-36. doi: 10.1158/0008-5472.CAN-10-1547. Epub 2010 Sep 7.
• [25] Serum alarm antiproteases in systemic sclerosis patients.Hum Immunol. 2017 Sep;78(9):559-564. doi: 10.1016/j.humimm.2017.06.002. Epub 2017 Jun 9.
• [26] A potential contribution of trappin-2 to the development of vasculopathy in systemic sclerosis.J Eur Acad Dermatol Venereol. 2019 Apr;33(4):753-760. doi: 10.1111/jdv.15387. Epub 2019 Jan 1.
• [27] Adenoviral E1A suppresses secretory leukoprotease inhibitor and elafin secretion in human alveolar epithelial cells and bronchial epithelial cells.Respiration. 2005 Nov-Dec;72(6):629-35. doi: 10.1159/000089579.
• [28] Expression and Clinical Significance of Elafin in Inflammatory Bowel Disease.Inflamm Bowel Dis. 2017 Dec;23(12):2134-2141. doi: 10.1097/MIB.0000000000001252.
• [29] Protective effects of elafin against adult asthma.Allergy Asthma Proc. 2016 Mar-Apr;37(2):15-24. doi: 10.2500/aap.2016.37.3932.
• [30] Genes specifically modulated in sensitized skins allow the detection of sensitizers in a reconstructed human skin modelDevelopment of the SENS-IS assay. Toxicol In Vitro. 2015 Jun;29(4):787-802.
• [31] Alpha1-antitrypsin gene therapy modulates cellular immunity and efficiently prevents type 1 diabetes in nonobese diabetic mice.Hum Gene Ther. 2006 Jun;17(6):625-34. doi: 10.1089/hum.2006.17.625.
• [32] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [33] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [34] 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.
• [35] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [36] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [37] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [38] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [39] Chemicals with weak skin sensitizing properties can be identified using low-density microarrays on immature dendritic cells. Toxicol Lett. 2007 Nov 1;174(1-3):98-109. doi: 10.1016/j.toxlet.2007.08.015. Epub 2007 Sep 5.
• [40] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [41] 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.
• [42] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [43] 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.