Details of Drug Off-Target (DOT)

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

• DOT Name: Kallikrein-8 (KLK8)
• Synonyms: hK8; EC 3.4.21.118; Neuropsin; NP; Ovasin; Serine protease 19; Serine protease TADG-14; Tumor-associated differentially expressed gene 14 protein
• Gene Name: KLK8
• UniProt ID: KLK8_HUMAN
• PDB ID: 5MS3; 5MS4
• EC Number: 3.4.21.118
• Pfam ID: PF00089
• Sequence:
  MGRPRPRAAKTWMFLLLLGGAWAGHSRAQEDKVLGGHECQPHSQPWQAALFQGQQLLCGG
  VLVGGNWVLTAAHCKKPKYTVRLGDHSLQNKDGPEQEIPVVQSIPHPCYNSSDVEDHNHD
  LMLLQLRDQASLGSKVKPISLADHCTQPGQKCTVSGWGTVTSPRENFPDTLNCAEVKIFP
  QKKCEDAYPGQITDGMVCAGSSKGADTCQGDSGGPLVCDGALQGITSWGSDPCGRSDKPG
  VYTNICRYLDWIKKIIGSKG
• Function: Serine protease which is capable of degrading a number of proteins such as casein, fibrinogen, kininogen, fibronectin and collagen type IV. Also cleaves L1CAM in response to increased neural activity. Induces neurite outgrowth and fasciculation of cultured hippocampal neurons. Plays a role in the formation and maturation of orphan and small synaptic boutons in the Schaffer-collateral pathway, regulates Schaffer-collateral long-term potentiation in the hippocampus and is required for memory acquisition and synaptic plasticity. Involved in skin desquamation and keratinocyte proliferation. Plays a role in the secondary phase of pathogenesis following spinal cord injury.
• Tissue Specificity: Isoform 1 is predominantly expressed in the pancreas. Isoform 2 is expressed in adult brain and hippocampus. Isoform 1 and isoform 2 are found in fetal brain and placenta. Detected in salivary gland, uterus, thymus, breast, testis and kidney but not in spleen, liver, lung or normal ovarian tissue. Displays an 11.5-fold increase in Alzheimer disease hippocampus compared to controls and is overexpressed in some ovarian carcinomas. Expressed at low levels in normal skin while high levels are found in psoriasis vulgaris, seborrheic keratosis, lichen planus and squamous cell carcinoma skin samples. Expressed in the keratinocytes.
• Reactome Pathway: Formation of the cornified envelope (R-HSA-6809371)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Kallikrein-8 (KLK8) affects the response to substance of Cisplatin.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Kallikrein-8 (KLK8).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Kallikrein-8 (KLK8).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Kallikrein-8 (KLK8).	[2]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Kallikrein-8 (KLK8).	[3]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Kallikrein-8 (KLK8).	[4]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Kallikrein-8 (KLK8).	[5]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Kallikrein-8 (KLK8).	[6]
Magnesium	DMU4ORS	Approved	Magnesium increases the activity of Kallikrein-8 (KLK8).	[7]
Potassium chloride	DMMTAJC	Approved	Potassium chloride increases the activity of Kallikrein-8 (KLK8).	[7]
Magnesium Sulfate	DMVEK07	Approved	Magnesium Sulfate increases the activity of Kallikrein-8 (KLK8).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Kallikrein-8 (KLK8).	[5]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Kallikrein-8 (KLK8).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Kallikrein-8 (KLK8).	[10]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Kallikrein-8 (KLK8).	[11]
Leupeptin	DMU075F	Investigative	Leupeptin decreases the activity of Kallikrein-8 (KLK8).	[7]
CHYMOSTATIN	DMT27QD	Investigative	CHYMOSTATIN decreases the activity of Kallikrein-8 (KLK8).	[7]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Arsenic alters transcriptional responses to Pseudomonas aeruginosa infection and decreases antimicrobial defense of human airway epithelial cells. Toxicol Appl Pharmacol. 2017 Sep 15;331:154-163.
• [3] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [4] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [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] 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.
• [7] Activation and enzymatic characterization of recombinant human kallikrein 8. Biol Chem. 2006 Jun;387(6):723-31. doi: 10.1515/BC.2006.091.
• [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] 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.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [11] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [12] 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.