Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIEA234)

• DOT Name: Kallikrein-6 (KLK6)
• Synonyms: EC 3.4.21.-; Neurosin; Protease M; SP59; Serine protease 18; Serine protease 9; Zyme
• Gene Name: KLK6
• UniProt ID: KLK6_HUMAN
• PDB ID: 1GVL; 1L2E; 1LO6; 3VFE; 4D8N; 5NX1; 5NX3; 6QFF; 6QFG; 6QFH; 6QH9; 6QHA; 6QHB; 6QHC; 6SKB; 6SKC; 6SKD; 7QFT; 7QFV; 7QHZ; 7QI0
• EC Number: 3.4.21.-
• Pfam ID: PF00089
• Sequence:
  MKKLMVVLSLIAAAWAEEQNKLVHGGPCDKTSHPYQAALYTSGHLLCGGVLIHPLWVLTA
  AHCKKPNLQVFLGKHNLRQRESSQEQSSVVRAVIHPDYDAASHDQDIMLLRLARPAKLSE
  LIQPLPLERDCSANTTSCHILGWGKTADGDFPDTIQCAYIHLVSREECEHAYPGQITQNM
  LCAGDEKYGKDSCQGDSGGPLVCGDHLRGLVSWGNIPCGSKEKPGVYTNVCRYTNWIQKT
  IQAK
• Function: Serine protease which exhibits a preference for Arg over Lys in the substrate P1 position and for Ser or Pro in the P2 position. Shows activity against amyloid precursor protein, myelin basic protein, gelatin, casein and extracellular matrix proteins such as fibronectin, laminin, vitronectin and collagen. Degrades alpha-synuclein and prevents its polymerization, indicating that it may be involved in the pathogenesis of Parkinson disease and other synucleinopathies. May be involved in regulation of axon outgrowth following spinal cord injury. Tumor cells treated with a neutralizing KLK6 antibody migrate less than control cells, suggesting a role in invasion and metastasis.
• Tissue Specificity: In fluids, highest levels found in milk of lactating women followed by cerebrospinal fluid, nipple aspirate fluid and breast cyst fluid. Also found in serum, seminal plasma and some amniotic fluids and breast tumor cytosolic extracts. Not detected in urine. At the tissue level, highest concentrations found in glandular tissues such as salivary glands followed by lung, colon, fallopian tube, placenta, breast, pituitary and kidney. Not detected in skin, spleen, bone, thyroid, heart, ureter, liver, muscle, endometrium, testis, pancreas, seminal vesicle, ovary, adrenals and prostate. In brain, detected in gray matter neurons (at protein level). Colocalizes with pathological inclusions such as Lewy bodies and glial cytoplasmic inclusions. Overexpressed in primary breast tumors but not expressed in metastatic tumors.

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
Methotrexate	DM2TEOL	Approved	Kallikrein-6 (KLK6) affects the response to substance of Methotrexate.	[16]

16 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 Kallikrein-6 (KLK6).	[1]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Kallikrein-6 (KLK6).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Kallikrein-6 (KLK6).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Kallikrein-6 (KLK6).	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Kallikrein-6 (KLK6).	[5]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Kallikrein-6 (KLK6).	[6]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Kallikrein-6 (KLK6).	[7]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Kallikrein-6 (KLK6).	[3]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Kallikrein-6 (KLK6).	[8]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Kallikrein-6 (KLK6).	[9]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Kallikrein-6 (KLK6).	[10]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Kallikrein-6 (KLK6).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Kallikrein-6 (KLK6).	[12]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of Kallikrein-6 (KLK6).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Kallikrein-6 (KLK6).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Kallikrein-6 (KLK6).	[15]

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 Kallikrein-6 (KLK6).	[13]

References

• [1] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [2] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [3] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [4] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [5] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [6] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [9] Dissecting progressive stages of 5-fluorouracil resistance in vitro using RNA expression profiling. Int J Cancer. 2004 Nov 1;112(2):200-12. doi: 10.1002/ijc.20401.
• [10] 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.
• [11] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] 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.
• [14] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] 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.