Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT79WJZZ)

• DOT Name: Dipeptidyl peptidase 1 (CTSC)
• Synonyms: EC 3.4.14.1; Cathepsin C; Cathepsin J; Dipeptidyl peptidase I; DPP-I; DPPI; Dipeptidyl transferase
• Gene Name: CTSC
• Related Disease:
  Papillon-Lefevre disease
  Ectodermal dysplasia
  Haim-Munk syndrome
  Periodontitis, aggressive 1
• UniProt ID: CATC_HUMAN
• PDB ID: 1K3B; 2DJF; 2DJG; 3PDF; 4CDC; 4CDD; 4CDE; 4CDF; 4OEL; 4OEM
• EC Number: 3.4.14.1
• Pfam ID: PF08773 ; PF00112
• Sequence:
  MGAGPSLLLAALLLLLSGDGAVRCDTPANCTYLDLLGTWVFQVGSSGSQRDVNCSVMGPQ
  EKKVVVYLQKLDTAYDDLGNSGHFTIIYNQGFEIVLNDYKWFAFFKYKEEGSKVTTYCNE
  TMTGWVHDVLGRNWACFTGKKVGTASENVYVNIAHLKNSQEKYSNRLYKYDHNFVKAINA
  IQKSWTATTYMEYETLTLGDMIRRSGGHSRKIPRPKPAPLTAEIQQKILHLPTSWDWRNV
  HGINFVSPVRNQASCGSCYSFASMGMLEARIRILTNNSQTPILSPQEVVSCSQYAQGCEG
  GFPYLIAGKYAQDFGLVEEACFPYTGTDSPCKMKEDCFRYYSSEYHYVGGFYGGCNEALM
  KLELVHHGPMAVAFEVYDDFLHYKKGIYHHTGLRDPFNPFELTNHAVLLVGYGTDSASGM
  DYWIVKNSWGTGWGENGYFRIRRGTDECAIESIAVAATPIPKL
• Function: Thiol protease. Has dipeptidylpeptidase activity. Active against a broad range of dipeptide substrates composed of both polar and hydrophobic amino acids. Proline cannot occupy the P1 position and arginine cannot occupy the P2 position of the substrate. Can act as both an exopeptidase and endopeptidase. Activates serine proteases such as elastase, cathepsin G and granzymes A and B.
• Tissue Specificity: Ubiquitous. Highly expressed in lung, kidney and placenta. Detected at intermediate levels in colon, small intestine, spleen and pancreas.
• KEGG Pathway:
  Lysosome (hsa04142)
  Apoptosis (hsa04210)
• Reactome Pathway:
  MHC class II antigen presentation (R-HSA-2132295)
  Cargo concentration in the ER (R-HSA-5694530)
  Neutrophil degranulation (R-HSA-6798695)
  COPII-mediated vesicle transport (R-HSA-204005)
• BioCyc Pathway: MetaCyc:HS03265-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Papillon-Lefevre disease	DIS3R7KX	Definitive	Autosomal recessive	[1]
Ectodermal dysplasia	DISLRS4M	Strong	Autosomal recessive	[2]
Haim-Munk syndrome	DISERGZL	Strong	Autosomal recessive	[3]
Periodontitis, aggressive 1	DISL7CZV	Limited	Unknown	[4]

30 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 Dipeptidyl peptidase 1 (CTSC).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Dipeptidyl peptidase 1 (CTSC).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Dipeptidyl peptidase 1 (CTSC).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dipeptidyl peptidase 1 (CTSC).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dipeptidyl peptidase 1 (CTSC).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Dipeptidyl peptidase 1 (CTSC).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Dipeptidyl peptidase 1 (CTSC).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dipeptidyl peptidase 1 (CTSC).	[11]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Dipeptidyl peptidase 1 (CTSC).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Dipeptidyl peptidase 1 (CTSC).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Dipeptidyl peptidase 1 (CTSC).	[14]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Dipeptidyl peptidase 1 (CTSC).	[6]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Dipeptidyl peptidase 1 (CTSC).	[15]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Dipeptidyl peptidase 1 (CTSC).	[16]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Dipeptidyl peptidase 1 (CTSC).	[17]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Dipeptidyl peptidase 1 (CTSC).	[6]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Dipeptidyl peptidase 1 (CTSC).	[6]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Dipeptidyl peptidase 1 (CTSC).	[6]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the expression of Dipeptidyl peptidase 1 (CTSC).	[6]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of Dipeptidyl peptidase 1 (CTSC).	[18]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil decreases the expression of Dipeptidyl peptidase 1 (CTSC).	[6]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Dipeptidyl peptidase 1 (CTSC).	[19]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Dipeptidyl peptidase 1 (CTSC).	[20]
DNCB	DMDTVYC	Phase 2	DNCB decreases the expression of Dipeptidyl peptidase 1 (CTSC).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Dipeptidyl peptidase 1 (CTSC).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Dipeptidyl peptidase 1 (CTSC).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Dipeptidyl peptidase 1 (CTSC).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Dipeptidyl peptidase 1 (CTSC).	[5]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Dipeptidyl peptidase 1 (CTSC).	[25]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Dipeptidyl peptidase 1 (CTSC).	[26]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Novel point mutations, deletions, and polymorphisms in the cathepsin C gene in nine families from Europe and North Africa with Papillon-Lefvre syndrome. J Invest Dermatol. 2001 Dec;117(6):1657-61. doi: 10.1046/j.0022-202x.2001.01595.x.
• [3] Dipeptidyl peptidase I is required for the processing and activation of granzymes A and B in vivo. Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8627-32. doi: 10.1073/pnas.96.15.8627.
• [4] The role of cathepsin C in Papillon-Lefvre syndrome, prepubertal periodontitis, and aggressive periodontitis. Hum Mutat. 2004 Mar;23(3):222-8. doi: 10.1002/humu.10314.
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• [10] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [11] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [12] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [13] 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.
• [14] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [15] Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix. J Nutr Biochem. 2007 Aug;18(8):541-52. doi: 10.1016/j.jnutbio.2006.11.002. Epub 2007 Feb 22.
• [16] Niclosamide, an oral antihelmintic drug, exhibits antimetastatic activity in hepatocellular carcinoma cells through downregulating twist-mediated CD10 expression. Environ Toxicol. 2018 Jun;33(6):659-669.
• [17] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [18] Controlled diesel exhaust and allergen coexposure modulates microRNA and gene expression in humans: Effects on inflammatory lung markers. J Allergy Clin Immunol. 2016 Dec;138(6):1690-1700. doi: 10.1016/j.jaci.2016.02.038. Epub 2016 Apr 24.
• [19] 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.
• [20] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [21] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [22] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [23] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [24] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [25] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [26] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.