Details of Drug Off-Target (DOT)

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

• DOT Name: Serine protease inhibitor Kazal-type 6 (SPINK6)
• Synonyms: Kallikrein inhibitor
• Gene Name: SPINK6
• Related Disease:
  Atopic dermatitis
  Enterocolitis
  leukaemia
  Leukemia
  Hereditary angioedema
  Nasopharyngeal carcinoma
  Neoplasm
• UniProt ID: ISK6_HUMAN
• PDB ID: 2N52
• Pfam ID: PF00050
• Sequence:
  MKLSGMFLLLSLALFCFLTGVFSQGGQVDCGEFQDPKVYCTRESNPHCGSDGQTYGNKCA
  FCKAIVKSGGKISLKHPGKC
• Function: Serine protease inhibitor selective for kallikreins. Efficiently inhibits KLK4, KLK5, KLK6, KLK7, KLK12, KLK13 and KLK14. Doesn't inhibit KLK8.
• Reactome Pathway: Formation of the cornified envelope (R-HSA-6809371)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atopic dermatitis	DISTCP41	Strong	Altered Expression	[1]
Enterocolitis	DISYACTL	Strong	Biomarker	[2]
leukaemia	DISS7D1V	Strong	Biomarker	[3]
Leukemia	DISNAKFL	Strong	Biomarker	[3]
Hereditary angioedema	DIS8X53J	Disputed	Genetic Variation	[4]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[5]
Neoplasm	DISZKGEW	Limited	Altered Expression	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Serine protease inhibitor Kazal-type 6 (SPINK6).	[6]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Serine protease inhibitor Kazal-type 6 (SPINK6).	[7]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Serine protease inhibitor Kazal-type 6 (SPINK6).	[9]

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 decreases the methylation of Serine protease inhibitor Kazal-type 6 (SPINK6).	[8]

References

• [1] Isolation of SPINK6 in human skin: selective inhibitor of kallikrein-related peptidases.J Biol Chem. 2010 Oct 15;285(42):32174-81. doi: 10.1074/jbc.M109.091850. Epub 2010 Jul 28.
• [2] The role of plasma high molecular weight kininogen in experimental intestinal and systemic inflammation.Arch Med Res. 2005 Jan-Feb;36(1):87-95. doi: 10.1016/j.arcmed.2005.02.001.
• [3] Blocking the proliferation of human tumor cell lines by peptidase inhibitors from Bauhinia seeds.Planta Med. 2013 Mar;79(3-4):227-35. doi: 10.1055/s-0032-1328156. Epub 2013 Jan 23.
• [4] Novel MASP-2 inhibitors developed via directed evolution of human TFPI1 are potent lectin pathway inhibitors.J Biol Chem. 2019 May 17;294(20):8227-8237. doi: 10.1074/jbc.RA119.008315. Epub 2019 Apr 5.
• [5] SPINK6 Promotes Metastasis of Nasopharyngeal Carcinoma via Binding and Activation of Epithelial Growth Factor Receptor.Cancer Res. 2017 Jan 15;77(2):579-589. doi: 10.1158/0008-5472.CAN-16-1281. Epub 2016 Sep 26.
• [6] 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.
• [7] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [8] 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.
• [9] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.