Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9C197Z)

• DOT Name: Matrix metalloproteinase-14 (MMP14)
• Synonyms: MMP-14; EC 3.4.24.80; MMP-X1; Membrane-type matrix metalloproteinase 1; MT-MMP 1; MTMMP1; Membrane-type-1 matrix metalloproteinase; MT1-MMP; MT1MMP
• Gene Name: MMP14
• Related Disease:
  Winchester syndrome
  Multicentric osteolysis-nodulosis-arthropathy spectrum
• UniProt ID: MMP14_HUMAN
• PDB ID: 1BQQ; 1BUV; 2MQS; 3C7X; 3MA2; 3X23; 4P3C; 4P3D; 4QXU; 5H0U; 6CLZ; 6CM1
• EC Number: 3.4.24.80
• Pfam ID: PF11857 ; PF00045 ; PF00413 ; PF01471
• Sequence:
  MSPAPRPPRCLLLPLLTLGTALASLGSAQSSSFSPEAWLQQYGYLPPGDLRTHTQRSPQS
  LSAAIAAMQKFYGLQVTGKADADTMKAMRRPRCGVPDKFGAEIKANVRRKRYAIQGLKWQ
  HNEITFCIQNYTPKVGEYATYEAIRKAFRVWESATPLRFREVPYAYIREGHEKQADIMIF
  FAEGFHGDSTPFDGEGGFLAHAYFPGPNIGGDTHFDSAEPWTVRNEDLNGNDIFLVAVHE
  LGHALGLEHSSDPSAIMAPFYQWMDTENFVLPDDDRRGIQQLYGGESGFPTKMPPQPRTT
  SRPSVPDKPKNPTYGPNICDGNFDTVAMLRGEMFVFKERWFWRVRNNQVMDGYPMPIGQF
  WRGLPASINTAYERKDGKFVFFKGDKHWVFDEASLEPGYPKHIKELGRGLPTDKIDAALF
  WMPNGKTYFFRGNKYYRFNEELRAVDSEYPKNIKVWEGIPESPRGSFMGSDEVFTYFYKG
  NKYWKFNNQKLKVEPGYPKSALRDWMGCPSGGRPDEGTEEETEVIIIEVDEEGGGAVSAA
  AVVLPVLLLLLVLAVGLAVFFFRRHGTPRRLLYCQRSLLDKV
• Function: Endopeptidase that degrades various components of the extracellular matrix such as collagen. Activates progelatinase A. Essential for pericellular collagenolysis and modeling of skeletal and extraskeletal connective tissues during development. May be involved in actin cytoskeleton reorganization by cleaving PTK7. Acts as a positive regulator of cell growth and migration via activation of MMP15. Involved in the formation of the fibrovascular tissues in association with pro-MMP2. Cleaves ADGRB1 to release vasculostatin-40 which inhibits angiogenesis.
• Tissue Specificity: Expressed in stromal cells of colon, breast, and head and neck. Expressed in lung tumors.
• KEGG Pathway:
  TNF sig.ling pathway (hsa04668)
  GnRH sig.ling pathway (hsa04912)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
• Reactome Pathway:
  Degradation of the extracellular matrix (R-HSA-1474228)
  Activation of Matrix Metalloproteinases (R-HSA-1592389)
  Collagen degradation (R-HSA-1442490)
• BioCyc Pathway: MetaCyc:ENSG00000157227-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Winchester syndrome	DISS4AF5	Moderate	Autosomal recessive	[1]
Multicentric osteolysis-nodulosis-arthropathy spectrum	DISG2NHG	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Pentoxifylline	DMU3DNC	Approved	Matrix metalloproteinase-14 (MMP14) increases the Collagen disorder ADR of Pentoxifylline.	[34]

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 Matrix metalloproteinase-14 (MMP14).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Matrix metalloproteinase-14 (MMP14).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Matrix metalloproteinase-14 (MMP14).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Matrix metalloproteinase-14 (MMP14).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Matrix metalloproteinase-14 (MMP14).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Matrix metalloproteinase-14 (MMP14).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Matrix metalloproteinase-14 (MMP14).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Matrix metalloproteinase-14 (MMP14).	[9]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Matrix metalloproteinase-14 (MMP14).	[10]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Matrix metalloproteinase-14 (MMP14).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Matrix metalloproteinase-14 (MMP14).	[9]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Matrix metalloproteinase-14 (MMP14).	[12]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of Matrix metalloproteinase-14 (MMP14).	[13]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Matrix metalloproteinase-14 (MMP14).	[14]
Ardeparin	DMYRX8B	Approved	Ardeparin decreases the expression of Matrix metalloproteinase-14 (MMP14).	[15]
Cysteamine	DMSYFM8	Approved	Cysteamine increases the expression of Matrix metalloproteinase-14 (MMP14).	[16]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Matrix metalloproteinase-14 (MMP14).	[17]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Matrix metalloproteinase-14 (MMP14).	[18]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Matrix metalloproteinase-14 (MMP14).	[19]
MRE-0094	DMQR23W	Phase 2	MRE-0094 decreases the expression of Matrix metalloproteinase-14 (MMP14).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Matrix metalloproteinase-14 (MMP14).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Matrix metalloproteinase-14 (MMP14).	[23]
Beta-aminopropionitrile	DMSJ2I6	Preclinical	Beta-aminopropionitrile decreases the activity of Matrix metalloproteinase-14 (MMP14).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Matrix metalloproteinase-14 (MMP14).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Matrix metalloproteinase-14 (MMP14).	[26]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Matrix metalloproteinase-14 (MMP14).	[27]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Matrix metalloproteinase-14 (MMP14).	[28]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Matrix metalloproteinase-14 (MMP14).	[29]
Manganese	DMKT129	Investigative	Manganese decreases the expression of Matrix metalloproteinase-14 (MMP14).	[30]
acrolein	DMAMCSR	Investigative	acrolein increases the expression of Matrix metalloproteinase-14 (MMP14).	[31]
biochanin A	DM0HPWY	Investigative	biochanin A decreases the expression of Matrix metalloproteinase-14 (MMP14).	[32]
DEMETHOXYCURCUMIN	DMO5UGV	Investigative	DEMETHOXYCURCUMIN decreases the expression of Matrix metalloproteinase-14 (MMP14).	[17]
CGS 21680	DMZ0TGY	Investigative	CGS 21680 decreases the activity of Matrix metalloproteinase-14 (MMP14).	[20]
AGELADINE A	DMOJ3CW	Investigative	AGELADINE A decreases the activity of Matrix metalloproteinase-14 (MMP14).	[33]

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] Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome. Am J Hum Genet. 2012 Sep 7;91(3):572-6. doi: 10.1016/j.ajhg.2012.07.022. Epub 2012 Aug 23.
• [3] 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.
• [4] 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.
• [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] Regulation of vascular smooth muscle cell expression and function of matrix metalloproteinases is mediated by estrogen and progesterone exposure. J Vasc Surg. 2009 Jan;49(1):185-91. doi: 10.1016/j.jvs.2008.07.080. Epub 2008 Oct 1.
• [7] 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.
• [8] Arsenic trioxide (As2O3) inhibits invasion of HT1080 human fibrosarcoma cells: role of nuclear factor-kappaB and reactive oxygen species. J Cell Biochem. 2005 Aug 1;95(5):955-69. doi: 10.1002/jcb.20452.
• [9] 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.
• [10] Inhibition of invasion and induction of apoptosis by selenium in human malignant brain tumour cells in vitro. Int J Oncol. 2007 May;30(5):1263-71.
• [11] Effect of ovarian steroids on gene expression profile in human uterine microvascular endothelial cells. Fertil Steril. 2009 Aug;92(2):709-21.
• [12] Toxicoproteomics reveals an effect of clozapine on autophagy in human liver spheroids. Toxicol Mech Methods. 2023 Jun;33(5):401-410. doi: 10.1080/15376516.2022.2156005. Epub 2022 Dec 19.
• [13] Genomic and proteomic profiling of responses to toxic metals in human lung cells. Environ Health Perspect. 2003 May;111(6):825-35.
• [14] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [15] Biochemical and toxicological evaluation of nano-heparins in cell functional properties, proteasome activation and expression of key matrix molecules. Toxicol Lett. 2016 Jan 5;240(1):32-42. doi: 10.1016/j.toxlet.2015.10.005. Epub 2015 Oct 22.
• [16] Cysteamine suppresses invasion, metastasis and prolongs survival by inhibiting matrix metalloproteinases in a mouse model of human pancreatic cancer. PLoS One. 2012;7(4):e34437. doi: 10.1371/journal.pone.0034437. Epub 2012 Apr 20.
• [17] Curcumin, demethoxycurcumin and bisdemethoxycurcumin differentially inhibit cancer cell invasion through the down-regulation of MMPs and uPA. J Nutr Biochem. 2009 Feb;20(2):87-95. doi: 10.1016/j.jnutbio.2007.12.003. Epub 2008 May 20.
• [18] Genistein suppresses the invasive potential of human breast cancer cells through transcriptional regulation of metalloproteinases and their tissue inhibitors. Int J Oncol. 2005 Apr;26(4):1101-9. doi: 10.3892/ijo.26.4.1101.
• [19] Suppression of PMA-induced tumor cell invasion by dihydroartemisinin via inhibition of PKCalpha/Raf/MAPKs and NF-kappaB/AP-1-dependent mechanisms. Biochem Pharmacol. 2010 Jun 15;79(12):1714-26. doi: 10.1016/j.bcp.2010.02.003. Epub 2010 Feb 10.
• [20] Adenosine A(2A) receptors play a role in the pathogenesis of hepatic cirrhosis. Br J Pharmacol. 2006 Aug;148(8):1144-55. doi: 10.1038/sj.bjp.0706812. Epub 2006 Jun 19.
• [21] 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.
• [22] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [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] MCF-7 cells expressing nuclear associated lysyl oxidase-like 2 (LOXL2) exhibit an epithelial-to-mesenchymal transition (EMT) phenotype and are highly invasive in vitro. J Biol Chem. 2013 Oct 18;288(42):30000-30008. doi: 10.1074/jbc.C113.502310. Epub 2013 Sep 6.
• [25] Bisphenol A exposure induces metabolic disorders and enhances atherosclerosis in hyperlipidemic rabbits. J Appl Toxicol. 2015 Sep;35(9):1058-70.
• [26] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [27] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [28] Isoangustone A suppresses mesangial fibrosis and inflammation in human renal mesangial cells. Exp Biol Med (Maywood). 2011 Apr 1;236(4):435-44. doi: 10.1258/ebm.2010.010325. Epub 2011 Mar 2.
• [29] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
• [30] Signaling pathways mediating manganese-induced toxicity in human glioblastoma cells (u87). Neurochem Res. 2006 Oct;31(10):1211-8. doi: 10.1007/s11064-006-9178-8. Epub 2006 Oct 17.
• [31] Matrix metalloproteinase-14 mediates a phenotypic shift in the airways to increase mucin production. Am J Respir Crit Care Med. 2009 Nov 1;180(9):834-45. doi: 10.1164/rccm.200903-0328OC. Epub 2009 Aug 6.
• [32] Inhibition of matrix degrading enzymes and invasion in human glioblastoma (U87MG) cells by isoflavones. J Neurooncol. 2006 Sep;79(2):135-42. doi: 10.1007/s11060-006-9126-0. Epub 2006 Apr 6.
• [33] A one-pot synthesis and biological activity of ageladine A and analogues. J Med Chem. 2011 Apr 14;54(7):2492-503. doi: 10.1021/jm200039m. Epub 2011 Mar 17.
• [34] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.