Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT3YX5O)

• DOT Name: Cathepsin K (CTSK)
• Synonyms: EC 3.4.22.38; Cathepsin O; Cathepsin O2; Cathepsin X
• Gene Name: CTSK
• Related Disease: Pycnodysostosis
• UniProt ID: CATK_HUMAN
• PDB ID: 1ATK ; 1AU0 ; 1AU2 ; 1AU3 ; 1AU4 ; 1AYU ; 1AYV ; 1AYW ; 1BGO ; 1BY8 ; 1MEM ; 1NL6 ; 1NLJ ; 1Q6K ; 1SNK ; 1TU6 ; 1U9V ; 1U9W ; 1U9X ; 1VSN ; 1YK7 ; 1YK8 ; 1YT7 ; 2ATO ; 2AUX ; 2AUZ ; 2BDL ; 2R6N ; 3C9E ; 3H7D ; 3KW9 ; 3KWB ; 3KWZ ; 3KX1 ; 3O0U ; 3O1G ; 3OVZ ; 4DMX ; 4DMY ; 4N79 ; 4N8W ; 4X6H ; 4X6I ; 4X6J ; 4YV8 ; 4YVA ; 5J94 ; 5JA7 ; 5JH3 ; 5TDI ; 5TUN ; 5Z5O ; 6ASH ; 6HGY ; 6PXF ; 6QBS ; 6QL8 ; 6QLM ; 6QLW ; 6QLX ; 6QM0 ; 7NXL ; 7NXM ; 7PCK ; 7QBL ; 7QBM ; 7QBN ; 7QBO ; 8C3D
• EC Number: 3.4.22.38
• Pfam ID: PF08246 ; PF00112
• Sequence:
  MWGLKVLLLPVVSFALYPEEILDTHWELWKKTHRKQYNNKVDEISRRLIWEKNLKYISIH
  NLEASLGVHTYELAMNHLGDMTSEEVVQKMTGLKVPLSHSRSNDTLYIPEWEGRAPDSVD
  YRKKGYVTPVKNQGQCGSCWAFSSVGALEGQLKKKTGKLLNLSPQNLVDCVSENDGCGGG
  YMTNAFQYVQKNRGIDSEDAYPYVGQEESCMYNPTGKAAKCRGYREIPEGNEKALKRAVA
  RVGPVSVAIDASLTSFQFYSKGVYYDESCNSDNLNHAVLAVGYGIQKGNKHWIIKNSWGE
  NWGNKGYILMARNKNNACGIANLASFPKM
• Function: Thiol protease involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation. Involved in the release of thyroid hormone thyroxine (T4) by limited proteolysis of TG/thyroglobulin in the thyroid follicle lumen.
• Tissue Specificity: Predominantly expressed in osteoclasts (bones) . Expressed in thyroid epithelial cells .
• KEGG Pathway:
  Lysosome (hsa04142)
  Apoptosis (hsa04210)
  Osteoclast differentiation (hsa04380)
  Toll-like receptor sig.ling pathway (hsa04620)
  Rheumatoid arthritis (hsa05323)
• Reactome Pathway:
  Degradation of the extracellular matrix (R-HSA-1474228)
  Activation of Matrix Metalloproteinases (R-HSA-1592389)
  Trafficking and processing of endosomal TLR (R-HSA-1679131)
  MHC class II antigen presentation (R-HSA-2132295)
  RUNX1 regulates transcription of genes involved in differentiation of keratinocytes (R-HSA-8939242)
  Collagen degradation (R-HSA-1442490)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pycnodysostosis	DISMJ8CK	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Cathepsin K (CTSK).	[2]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Cathepsin K (CTSK).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cathepsin K (CTSK).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cathepsin K (CTSK).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cathepsin K (CTSK).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cathepsin K (CTSK).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cathepsin K (CTSK).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Cathepsin K (CTSK).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Cathepsin K (CTSK).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Cathepsin K (CTSK).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Cathepsin K (CTSK).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cathepsin K (CTSK).	[12]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Cathepsin K (CTSK).	[13]
Epinephrine	DM3KJBC	Approved	Epinephrine increases the expression of Cathepsin K (CTSK).	[14]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Cathepsin K (CTSK).	[15]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Cathepsin K (CTSK).	[16]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Cathepsin K (CTSK).	[18]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Cathepsin K (CTSK).	[19]

References

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• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] 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.
• [6] 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.
• [7] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [8] Dipeptidyl peptidase-4 inhibition prevents vascular aging in mice under chronic stress: Modulation of oxidative stress and inflammation. Chem Biol Interact. 2019 Dec 1;314:108842. doi: 10.1016/j.cbi.2019.108842. Epub 2019 Oct 2.
• [9] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [10] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [11] Primary Human Hepatocyte Spheroids as Tools to Study the Hepatotoxic Potential of Non-Pharmaceutical Chemicals. Int J Mol Sci. 2021 Oct 12;22(20):11005. doi: 10.3390/ijms222011005.
• [12] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] Effects of beta-adrenergic agonists on bone-resorbing activity in human osteoclast-like cells. Biochim Biophys Acta. 2003 May 12;1640(2-3):137-42.
• [15] 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.
• [16] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [17] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [18] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.
• [19] Probiotic Bacillus subtilis CW14 reduces disruption of the epithelial barrier and toxicity of ochratoxin A to Caco-2?cells. Food Chem Toxicol. 2019 Apr;126:25-33. doi: 10.1016/j.fct.2019.02.009. Epub 2019 Feb 11.