Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS2FPMI)

• DOT Name: Cartilage oligomeric matrix protein (COMP)
• Synonyms: COMP; Thrombospondin-5; TSP5
• Gene Name: COMP
• Related Disease:
  Chondrosarcoma
  Hyperglycemia
  Multiple epiphyseal dysplasia
  Non-insulin dependent diabetes
  Pseudoachondroplasia
  Type-1/2 diabetes
  Advanced cancer
  Alpha thalassemia
  Arthritis
  Bone development disease
  Bone osteosarcoma
  Colon cancer
  Colon carcinoma
  Crohn disease
  Depression
  Familial hypercholesterolemia
  Hepatocellular carcinoma
  Hypercholesterolemia, familial, 1
  Juvenile idiopathic arthritis
  Medulloblastoma
  Metastatic malignant neoplasm
  Morquio syndrome
  Multiple epiphyseal dysplasia type 1
  Myocardial infarction
  Neoplasm
  Obesity
  Osteochondrodysplasia
  Osteosarcoma
  Prostate cancer
  Prostate carcinoma
  Rheumatoid arthritis
  Triple negative breast cancer
  Diastrophic dysplasia
  High blood pressure
  Arteriosclerosis
  Asthma
  Atherosclerosis
  Cardiovascular disease
  Coronary atherosclerosis
  Coronary heart disease
  Glioma
  Knee osteoarthritis
  Melanoma
  Pancreatic cancer
  Systemic sclerosis
• UniProt ID: COMP_HUMAN
• PDB ID: 3FBY
• Pfam ID: PF11598 ; PF07645 ; PF02412 ; PF05735
• Sequence:
  MVPDTACVLLLTLAALGASGQGQSPLGSDLGPQMLRELQETNAALQDVRELLRQQVREIT
  FLKNTVMECDACGMQQSVRTGLPSVRPLLHCAPGFCFPGVACIQTESGARCGPCPAGFTG
  NGSHCTDVNECNAHPCFPRVRCINTSPGFRCEACPPGYSGPTHQGVGLAFAKANKQVCTD
  INECETGQHNCVPNSVCINTRGSFQCGPCQPGFVGDQASGCQRRAQRFCPDGSPSECHEH
  ADCVLERDGSRSCVCAVGWAGNGILCGRDTDLDGFPDEKLRCPERQCRKDNCVTVPNSGQ
  EDVDRDGIGDACDPDADGDGVPNEKDNCPLVRNPDQRNTDEDKWGDACDNCRSQKNDDQK
  DTDQDGRGDACDDDIDGDRIRNQADNCPRVPNSDQKDSDGDGIGDACDNCPQKSNPDQAD
  VDHDFVGDACDSDQDQDGDGHQDSRDNCPTVPNSAQEDSDHDGQGDACDDDDDNDGVPDS
  RDNCRLVPNPGQEDADRDGVGDVCQDDFDADKVVDKIDVCPENAEVTLTDFRAFQTVVLD
  PEGDAQIDPNWVVLNQGREIVQTMNSDPGLAVGYTAFNGVDFEGTFHVNTVTDDDYAGFI
  FGYQDSSSFYVVMWKQMEQTYWQANPFRAVAEPGIQLKAVKSSTGPGEQLRNALWHTGDT
  ESQVRLLWKDPRNVGWKDKKSYRWFLQHRPQVGYIRVRFYEGPELVADSNVVLDTTMRGG
  RLGVFCFSQENIIWANLRYRCNDTIPEDYETHQLRQA
• Function: Plays a role in the structural integrity of cartilage via its interaction with other extracellular matrix proteins such as the collagens and fibronectin. Can mediate the interaction of chondrocytes with the cartilage extracellular matrix through interaction with cell surface integrin receptors. Could play a role in the pathogenesis of osteoarthritis. Potent suppressor of apoptosis in both primary chondrocytes and transformed cells. Suppresses apoptosis by blocking the activation of caspase-3 and by inducing the IAP family of survival proteins (BIRC3, BIRC2, BIRC5 and XIAP). Essential for maintaining a vascular smooth muscle cells (VSMCs) contractile/differentiated phenotype under physiological and pathological stimuli. Maintains this phenotype of VSMCs by interacting with ITGA7.
• Tissue Specificity: Abundantly expressed in the chondrocyte extracellular matrix, and is also found in bone, tendon, ligament and synovium and blood vessels. Increased amounts are produced during late stages of osteoarthritis in the area adjacent to the main defect.
• KEGG Pathway:
  Phagosome (hsa04145)
  PI3K-Akt sig.ling pathway (hsa04151)
  Focal adhesion (hsa04510)
  ECM-receptor interaction (hsa04512)
  Cytoskeleton in muscle cells (hsa04820)
  Malaria (hsa05144)
  Human papillomavirus infection (hsa05165)
• Reactome Pathway:
  ECM proteoglycans (R-HSA-3000178)
  Integrin cell surface interactions (R-HSA-216083)

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chondrosarcoma	DIS4I7JB	Definitive	Altered Expression	[1]
Hyperglycemia	DIS0BZB5	Definitive	Altered Expression	[2]
Multiple epiphyseal dysplasia	DIS5FZLR	Definitive	Autosomal dominant	[3]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Altered Expression	[2]
Pseudoachondroplasia	DISVJW4A	Definitive	Autosomal dominant	[3]
Type-1/2 diabetes	DISIUHAP	Definitive	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Alpha thalassemia	DIS5XGK0	Strong	Genetic Variation	[5]
Arthritis	DIST1YEL	Strong	Altered Expression	[6]
Bone development disease	DISVKAZS	Strong	Genetic Variation	[7]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[8]
Colon cancer	DISVC52G	Strong	Biomarker	[9]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[9]
Crohn disease	DIS2C5Q8	Strong	Altered Expression	[10]
Depression	DIS3XJ69	Strong	Biomarker	[11]
Familial hypercholesterolemia	DISC06IX	Strong	Genetic Variation	[12]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Hypercholesterolemia, familial, 1	DISU411W	Strong	Biomarker	[13]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[14]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[15]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[9]
Morquio syndrome	DIS2Y2P2	Strong	Genetic Variation	[16]
Multiple epiphyseal dysplasia type 1	DISOJ4JU	Strong	Autosomal dominant	[17]
Myocardial infarction	DIS655KI	Strong	Altered Expression	[18]
Neoplasm	DISZKGEW	Strong	Biomarker	[19]
Obesity	DIS47Y1K	Strong	Biomarker	[20]
Osteochondrodysplasia	DIS9SPWW	Strong	Genetic Variation	[21]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[8]
Prostate cancer	DISF190Y	Strong	Biomarker	[22]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[22]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[23]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[24]
Diastrophic dysplasia	DISNTGP7	moderate	Biomarker	[25]
High blood pressure	DISY2OHH	moderate	Biomarker	[26]
Arteriosclerosis	DISK5QGC	Limited	Biomarker	[27]
Asthma	DISW9QNS	Limited	Biomarker	[28]
Atherosclerosis	DISMN9J3	Limited	Biomarker	[27]
Cardiovascular disease	DIS2IQDX	Limited	Biomarker	[29]
Coronary atherosclerosis	DISKNDYU	Limited	Altered Expression	[30]
Coronary heart disease	DIS5OIP1	Limited	Altered Expression	[30]
Glioma	DIS5RPEH	Limited	Biomarker	[31]
Knee osteoarthritis	DISLSNBJ	Limited	Biomarker	[32]
Melanoma	DIS1RRCY	Limited	Biomarker	[33]
Pancreatic cancer	DISJC981	Limited	Altered Expression	[34]
Systemic sclerosis	DISF44L6	Limited	Altered Expression	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Cartilage oligomeric matrix protein (COMP).	[36]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cartilage oligomeric matrix protein (COMP).	[37]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cartilage oligomeric matrix protein (COMP).	[38]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cartilage oligomeric matrix protein (COMP).	[39]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cartilage oligomeric matrix protein (COMP).	[40]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Cartilage oligomeric matrix protein (COMP).	[41]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Cartilage oligomeric matrix protein (COMP).	[42]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Cartilage oligomeric matrix protein (COMP).	[43]

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 increases the methylation of Cartilage oligomeric matrix protein (COMP).	[44]

References

• [1] COMP mutations: domain-dependent relationship between abnormal chondrocyte trafficking and clinical PSACH and MED phenotypes.J Cell Biochem. 2008 Feb 15;103(3):778-87. doi: 10.1002/jcb.21445.
• [2] Cartilage Oligomeric Matrix Protein Levels in Type 2 Diabetes Associated with Primary Knee Osteoarthritis Patients.Genet Test Mol Biomarkers. 2019 Jan;23(1):16-22. doi: 10.1089/gtmb.2018.0184. Epub 2018 Dec 8.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] Resolvin D1 prevents epithelial-mesenchymal transition and reduces the stemness features of hepatocellular carcinoma by inhibiting paracrine of cancer-associated fibroblast-derived COMP.J Exp Clin Cancer Res. 2019 Apr 18;38(1):170. doi: 10.1186/s13046-019-1163-6.
• [5] Identification of -globin chain variants: a report from Iran.Arch Iran Med. 2012 Sep;15(9):564-7.
• [6] Comparative study of methotrexate and human umbilical cord mesenchymal stem cell transplantation in the treatment of rheumatoid arthritis.J Biol Regul Homeost Agents. 2018 May-Jun;32(3):599-605.
• [7] A pilot study of gene testing of genetic bone dysplasia using targeted next-generation sequencing.J Hum Genet. 2015 Dec;60(12):769-76. doi: 10.1038/jhg.2015.112. Epub 2015 Sep 17.
• [8] Gene expression profile of the whole Mediator complex in human osteosarcoma and normal osteoblasts.Med Oncol. 2013 Dec;30(4):739. doi: 10.1007/s12032-013-0739-9. Epub 2013 Oct 8.
• [9] Increasing Incidence of Colon Cancer in the Young: Assessing the Tumor Biology.J Am Coll Surg. 2019 Jul;229(1):79-90. doi: 10.1016/j.jamcollsurg.2019.03.022. Epub 2019 Apr 14.
• [10] Association Between Plasma Level of Collagen Type III Alpha 1 Chain and Development of Strictures in Pediatric Patients With Crohn's Disease.Clin Gastroenterol Hepatol. 2019 Aug;17(9):1799-1806. doi: 10.1016/j.cgh.2018.09.008. Epub 2018 Sep 10.
• [11] Can targeted metabolomics predict depression recovery? Results from the CO-MED trial.Transl Psychiatry. 2019 Jan 16;9(1):11. doi: 10.1038/s41398-018-0349-6.
• [12] Diagnosis of families with familial hypercholesterolaemia and/or Apo B-100 defect by means of DNA analysis of LDL-receptor gene mutations.J Inherit Metab Dis. 2007 Apr;30(2):239-47. doi: 10.1007/s10545-007-0563-5. Epub 2007 Mar 8.
• [13] Genetic diagnosis of familial hypercholesterolemia in affected relatives using pedigree tracing.Clin Biochem. 1996 Aug;29(4):371-7. doi: 10.1016/0009-9120(96)00017-3.
• [14] Juvenile idiopathic arthritis patients have a distinct cartilage and bone biomarker profile that differs from healthy and knee-injured children.Clin Exp Rheumatol. 2020 Mar-Apr;38(2):355-365. doi: 10.55563/clinexprheumatol/ck090i. Epub 2019 Oct 30.
• [15] miR-219 inhibits the proliferation, migration and invasion of medulloblastoma cells by targeting CD164.Int J Mol Med. 2014 Jul;34(1):237-43. doi: 10.3892/ijmm.2014.1749. Epub 2014 Apr 22.
• [16] Genetic analysis and serum level of cartilage oligomeric matrix protein in patients with pseudoachondroplasia.Chin Med J (Engl). 2010 Aug;123(16):2181-4.
• [17] Cartilage oligomeric matrix protein-deficient mice have normal skeletal development. Mol Cell Biol. 2002 Jun;22(12):4366-71. doi: 10.1128/MCB.22.12.4366-4371.2002.
• [18] Extracellular matrix markers and risk of myocardial infarction: The HUNT Study in Norway.Eur J Prev Cardiol. 2017 Jul;24(11):1161-1167. doi: 10.1177/2047487317703826. Epub 2017 Apr 21.
• [19] Cartilage Oligomeric Matrix Protein initiates cancer stem cells through activation of Jagged1-Notch3 signaling.Matrix Biol. 2019 Aug;81:107-121. doi: 10.1016/j.matbio.2018.11.007. Epub 2018 Nov 28.
• [20] Knocking out or pharmaceutical inhibition of fatty acid binding protein 4 (FABP4) alleviates osteoarthritis induced by high-fat diet in mice.Osteoarthritis Cartilage. 2018 Jun;26(6):824-833. doi: 10.1016/j.joca.2018.03.002. Epub 2018 Mar 13.
• [21] Exome sequencing revealed a p.G299R mutation in the COMP gene in an Iranian family suffering from pseudoachondroplasia.J Gene Med. 2019 Aug;21(8):e3103. doi: 10.1002/jgm.3103. Epub 2019 Jul 11.
• [22] Cartilage oligomeric matrix protein in patients with osteoarthritis is independently associated with metastatic disease in prostate cancer.Oncotarget. 2019 Jul 30;10(46):4776-4785. doi: 10.18632/oncotarget.27113. eCollection 2019 Jul 30.
• [23] Cartilage oligomeric matrix protein forms protein complexes with synovial lubricin via non-covalent and covalent interactions.Osteoarthritis Cartilage. 2017 Sep;25(9):1496-1504. doi: 10.1016/j.joca.2017.03.016. Epub 2017 Apr 1.
• [24] Pathological expression of tissue factor confers promising antitumor response to a novel therapeutic antibody SC1 in triple negative breast cancer and pancreatic adenocarcinoma.Oncotarget. 2017 Jul 10;8(35):59086-59102. doi: 10.18632/oncotarget.19175. eCollection 2017 Aug 29.
• [25] A compound heterozygote of novel and recurrent DTDST mutations results in a novel intermediate phenotype of Desbuquois dysplasia, diastrophic dysplasia, and recessive form of multiple epiphyseal dysplasia.J Hum Genet. 2008;53(8):764-768. doi: 10.1007/s10038-008-0305-z. Epub 2008 Jun 14.
• [26] Modulation of Sympathetic Overactivity to Treat Resistant Hypertension.Curr Hypertens Rep. 2018 Sep 7;20(11):92. doi: 10.1007/s11906-018-0893-8.
• [27] Cartilage Oligomeric Matrix Protein Associates With a Vulnerable Plaque Phenotype in Human Atherosclerotic Plaques.Stroke. 2019 Nov;50(11):3289-3292. doi: 10.1161/STROKEAHA.119.026457. Epub 2019 Sep 9.
• [28] Clinical efficacy of implementing Bio Immune(G)ene MEDicine in the treatment of chronic asthma with the objective of reducing or removing effectively corticosteroid therapy: A novel approach and promising results.Exp Ther Med. 2018 Jun;15(6):5133-5140. doi: 10.3892/etm.2018.6019. Epub 2018 Apr 2.
• [29] BARI 2D: A Reanalysis Focusing on Cardiovascular Events.Mayo Clin Proc. 2019 Nov;94(11):2249-2262. doi: 10.1016/j.mayocp.2019.04.015. Epub 2019 Oct 4.
• [30] Altered serum level of cartilage oligomeric matrix protein and its association with coronary calcification in patients with coronary heart disease.J Geriatr Cardiol. 2017 Feb;14(2):87-92. doi: 10.11909/j.issn.1671-5411.2017.02.002.
• [31] Therapeutic efficacy of vinorelbine against pediatric and adult central nervous system tumors.Cancer Chemother Pharmacol. 1998;42(6):479-82. doi: 10.1007/s002800050848.
• [32] COMP in the Infrapatellar Fat Pad-Results of a Prospective Histological, Immunohistological, and Biochemical Case-Control Study.J Orthop Res. 2020 Apr;38(4):747-758. doi: 10.1002/jor.24514. Epub 2019 Nov 17.
• [33] An engineered PD-1-based and MMP-2/9-oriented fusion protein exerts potent antitumor effects against melanoma.BMB Rep. 2018 Nov;51(11):572-577. doi: 10.5483/BMBRep.2018.51.11.076.
• [34] COMP is selectively up-regulated in degenerating acinar cells in chronic pancreatitis and in chronic-pancreatitis-like lesions in pancreatic cancer.Scand J Gastroenterol. 2003 Feb;38(2):207-15. doi: 10.1080/00365520310000717.
• [35] Cartilage oligomeric matrix protein expression in systemic sclerosis reveals heterogeneity of dermal fibroblast responses to transforming growth factor beta.Ann Rheum Dis. 2009 Mar;68(3):435-41. doi: 10.1136/ard.2007.086850. Epub 2008 Apr 13.
• [36] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [37] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [38] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [39] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [40] 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.
• [41] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [42] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [43] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [44] 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.