Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT61IIAO)

• DOT Name: Serine protease inhibitor Kazal-type 5 (SPINK5)
• Synonyms: Lympho-epithelial Kazal-type-related inhibitor; LEKTI
• Gene Name: SPINK5
• Related Disease:
  Advanced cancer
  Peeling skin syndrome 1
  Carcinoma of esophagus
  Endometritis
  Esophageal cancer
  IgE responsiveness, atopic
  Malaria
  Nasal polyp
  Neoplasm
  Neoplasm of esophagus
  Netherton syndrome
  Non-syndromic ichthyosis
  Polyp
  Prostate cancer
  Prostate neoplasm
  Psoriasis
  Skin disease
  Squamous cell carcinoma
  Trichohepatoenteric syndrome
  Congenital ichthyosiform erythroderma
  Craniosynostosis
  Food allergy
  Recessive X-linked ichthyosis
  Eosinophilic esophagitis
• UniProt ID: ISK5_HUMAN
• PDB ID: 1H0Z; 1HDL; 1UUC; 1UVF; 1UVG; 5YHN
• Pfam ID: PF00050
• Sequence:
  MKIATVSVLLPLALCLIQDAASKNEDQEMCHEFQAFMKNGKLFCPQDKKFFQSLDGIMFI
  NKCATCKMILEKEAKSQKRARHLARAPKATAPTELNCDDFKKGERDGDFICPDYYEAVCG
  TDGKTYDNRCALCAENAKTGSQIGVKSEGECKSSNPEQDVCSAFRPFVRDGRLGCTREND
  PVLGPDGKTHGNKCAMCAELFLKEAENAKREGETRIRRNAEKDFCKEYEKQVRNGRLFCT
  RESDPVRGPDGRMHGNKCALCAEIFKQRFSEENSKTDQNLGKAEEKTKVKREIVKLCSQY
  QNQAKNGILFCTRENDPIRGPDGKMHGNLCSMCQAYFQAENEEKKKAEARARNKRESGKA
  TSYAELCSEYRKLVRNGKLACTRENDPIQGPDGKVHGNTCSMCEVFFQAEEEEKKKKEGK
  SRNKRQSKSTASFEELCSEYRKSRKNGRLFCTRENDPIQGPDGKMHGNTCSMCEAFFQQE
  ERARAKAKREAAKEICSEFRDQVRNGTLICTREHNPVRGPDGKMHGNKCAMCASVFKLEE
  EEKKNDKEEKGKVEAEKVKREAVQELCSEYRHYVRNGRLPCTRENDPIEGLDGKIHGNTC
  SMCEAFFQQEAKEKERAEPRAKVKREAEKETCDEFRRLLQNGKLFCTRENDPVRGPDGKT
  HGNKCAMCKAVFQKENEERKRKEEEDQRNAAGHGSSGGGGGNTQDECAEYREQMKNGRLS
  CTRESDPVRDADGKSYNNQCTMCKAKLEREAERKNEYSRSRSNGTGSESGKDTCDEFRSQ
  MKNGKLICTRESDPVRGPDGKTHGNKCTMCKEKLEREAAEKKKKEDEDRSNTGERSNTGE
  RSNDKEDLCREFRSMQRNGKLICTRENNPVRGPYGKMHINKCAMCQSIFDREANERKKKD
  EEKSSSKPSNNAKDECSEFRNYIRNNELICPRENDPVHGADGKFYTNKCYMCRAVFLTEA
  LERAKLQEKPSHVRASQEEDSPDSFSSLDSEMCKDYRVLPRIGYLCPKDLKPVCGDDGQT
  YNNPCMLCHENLIRQTNTHIRSTGKCEESSTPGTTAASMPPSDE
• Function: Serine protease inhibitor, probably important for the anti-inflammatory and/or antimicrobial protection of mucous epithelia. Contribute to the integrity and protective barrier function of the skin by regulating the activity of defense-activating and desquamation-involved proteases. Inhibits KLK5, it's major target, in a pH-dependent manner. Inhibits KLK7, KLK14 CASP14, and trypsin.
• Tissue Specificity: Highly expressed in the thymus and stratum corneum. Also found in the oral mucosa, parathyroid gland, Bartholin's glands, tonsils, and vaginal epithelium. Very low levels are detected in lung, kidney, and prostate.
• Reactome Pathway: Formation of the cornified envelope (R-HSA-6809371)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Peeling skin syndrome 1	DIS35574	Definitive	Genetic Variation	[2]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[3]
Endometritis	DISHGJ6G	Strong	Biomarker	[4]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[3]
IgE responsiveness, atopic	DISAE27V	Strong	Biomarker	[5]
Malaria	DISQ9Y50	Strong	Biomarker	[6]
Nasal polyp	DISLP3XE	Strong	Altered Expression	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[3]
Netherton syndrome	DISQ95FU	Strong	Autosomal recessive	[8]
Non-syndromic ichthyosis	DISZ9QBQ	Strong	Genetic Variation	[9]
Polyp	DISRSLYF	Strong	Altered Expression	[10]
Prostate cancer	DISF190Y	Strong	Biomarker	[11]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[11]
Psoriasis	DIS59VMN	Strong	Altered Expression	[12]
Skin disease	DISDW8R6	Strong	Genetic Variation	[13]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[14]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[15]
Congenital ichthyosiform erythroderma	DISV8HQX	moderate	Biomarker	[16]
Craniosynostosis	DIS6J405	moderate	Altered Expression	[17]
Food allergy	DISMQ1BP	moderate	Genetic Variation	[18]
Recessive X-linked ichthyosis	DISZY56W	moderate	Genetic Variation	[19]
Eosinophilic esophagitis	DISR8WSB	Limited	Altered Expression	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Serine protease inhibitor Kazal-type 5 (SPINK5).	[21]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Serine protease inhibitor Kazal-type 5 (SPINK5).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Serine protease inhibitor Kazal-type 5 (SPINK5).	[23]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Serine protease inhibitor Kazal-type 5 (SPINK5).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Serine protease inhibitor Kazal-type 5 (SPINK5).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Serine protease inhibitor Kazal-type 5 (SPINK5).	[28]

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 increases the methylation of Serine protease inhibitor Kazal-type 5 (SPINK5).	[25]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Serine protease inhibitor Kazal-type 5 (SPINK5).	[27]

References

• [1] Adaptive Estimation of Personalized Maximum Tolerated Dose in Cancer Phase I Clinical Trials Based on All Toxicities and Individual Genomic Profile.PLoS One. 2017 Jan 26;12(1):e0170187. doi: 10.1371/journal.pone.0170187. eCollection 2017.
• [2] Netherton syndrome with extensive skin peeling and failure to thrive due to a homozygous frameshift mutation in SPINK5.Dermatology. 2005;210(4):308-14. doi: 10.1159/000084755.
• [3] A novel tumor suppressor SPINK5 targets Wnt/-catenin signaling pathway in esophageal cancer.Cancer Med. 2019 May;8(5):2360-2371. doi: 10.1002/cam4.2078. Epub 2019 Mar 13.
• [4] Genomic breeding values, SNP effects and gene identification for disease traits in cow training sets.Anim Genet. 2018 Jun;49(3):178-192. doi: 10.1111/age.12661. Epub 2018 Apr 6.
• [5] Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families.J Invest Dermatol. 2002 Feb;118(2):352-61. doi: 10.1046/j.1523-1747.2002.01603.x.
• [6] Whole-genome sequencing reveals high complexity of copy number variation at insecticide resistance loci in malaria mosquitoes.Genome Res. 2019 Aug;29(8):1250-1261. doi: 10.1101/gr.245795.118. Epub 2019 Jul 25.
• [7] Low SPINK5 expression in chronic rhinosinusitis.Laryngoscope. 2012 Jun;122(6):1198-204. doi: 10.1002/lary.23300. Epub 2012 May 8.
• [8] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [9] Activography reveals aberrant proteolysis in desquamating diseases of differing backgrounds.Exp Dermatol. 2019 Jan;28(1):86-89. doi: 10.1111/exd.13832.
• [10] Epithelial genes in chronic rhinosinusitis with and without nasal polyps.Am J Rhinol. 2008 May-Jun;22(3):228-34. doi: 10.2500/ajr.2008.22.3162.
• [11] Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
• [12] TNF- and IL-17A induce the expression of lympho-epithelial Kazal-type inhibitor in epidermal keratinocytes.J Dermatol Sci. 2019 Oct;96(1):26-32. doi: 10.1016/j.jdermsci.2019.08.007. Epub 2019 Aug 21.
• [13] A heterozygous null mutation combined with the G1258A polymorphism of SPINK5 causes impaired LEKTI function and abnormal expression of skin barrier proteins.Br J Dermatol. 2009 Aug;161(2):404-12. doi: 10.1111/j.1365-2133.2009.09231.x. Epub 2009 May 12.
• [14] An integrated methylation and gene expression microarray analysis reveals significant prognostic biomarkers in oral squamous cell carcinoma.Oncol Rep. 2018 Nov;40(5):2637-2647. doi: 10.3892/or.2018.6702. Epub 2018 Sep 12.
• [15] Netherton's syndrome and lepromatous leprosy: a mere coincidence?.Int J Dermatol. 2013 Feb;52(2):186-90. doi: 10.1111/j.1365-4632.2012.05620.x.
• [16] LEKTI domains D6, D7 and D8+9 serve as substrates for transglutaminase 1: implications for targeted therapy of Netherton syndrome.Br J Dermatol. 2019 Nov;181(5):999-1008. doi: 10.1111/bjd.17820. Epub 2019 Jun 6.
• [17] Endogenous Protease Inhibitors in Airway Epithelial Cells Contribute to Eosinophilic Chronic Rhinosinusitis.Am J Respir Crit Care Med. 2017 Mar 15;195(6):737-747. doi: 10.1164/rccm.201603-0529OC.
• [18] Genetic determinants of paediatric food allergy: A systematic review.Allergy. 2019 Sep;74(9):1631-1648. doi: 10.1111/all.13767. Epub 2019 Apr 2.
• [19] Skin Barrier Function Is Not Impaired and Kallikrein 7 Gene Polymorphism Is Frequently Observed in Korean X-linked Ichthyosis Patients Diagnosed by Fluorescence in Situ Hybridization and Array Comparative Genomic Hybridization.J Korean Med Sci. 2016 Aug;31(8):1307-18. doi: 10.3346/jkms.2016.31.8.1307. Epub 2016 May 20.
• [20] Active eosinophilic esophagitis is characterized by epithelial barrier defects and eosinophil extracellular trap formation.Allergy. 2015 Apr;70(4):443-52. doi: 10.1111/all.12570. Epub 2015 Jan 26.
• [21] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [22] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [23] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [24] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [25] 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.
• [26] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [27] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [28] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.