Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSFQ2BJ)

• DOT Name: Matrix metalloproteinase-16 (MMP16)
• Synonyms: MMP-16; EC 3.4.24.-; MMP-X2; Membrane-type matrix metalloproteinase 3; MT-MMP 3; MTMMP3; Membrane-type-3 matrix metalloproteinase; MT3-MMP; MT3MMP
• Gene Name: MMP16
• UniProt ID: MMP16_HUMAN
• PDB ID: 1RM8
• EC Number: 3.4.24.-
• Pfam ID: PF11857 ; PF00045 ; PF00413 ; PF01471
• Sequence:
  MILLTFSTGRRLDFVHHSGVFFLQTLLWILCATVCGTEQYFNVEVWLQKYGYLPPTDPRM
  SVLRSAETMQSALAAMQQFYGINMTGKVDRNTIDWMKKPRCGVPDQTRGSSKFHIRRKRY
  ALTGQKWQHKHITYSIKNVTPKVGDPETRKAIRRAFDVWQNVTPLTFEEVPYSELENGKR
  DVDITIIFASGFHGDSSPFDGEGGFLAHAYFPGPGIGGDTHFDSDEPWTLGNPNHDGNDL
  FLVAVHELGHALGLEHSNDPTAIMAPFYQYMETDNFKLPNDDLQGIQKIYGPPDKIPPPT
  RPLPTVPPHRSIPPADPRKNDRPKPPRPPTGRPSYPGAKPNICDGNFNTLAILRREMFVF
  KDQWFWRVRNNRVMDGYPMQITYFWRGLPPSIDAVYENSDGNFVFFKGNKYWVFKDTTLQ
  PGYPHDLITLGSGIPPHGIDSAIWWEDVGKTYFFKGDRYWRYSEEMKTMDPGYPKPITVW
  KGIPESPQGAFVHKENGFTYFYKGKEYWKFNNQILKVEPGYPRSILKDFMGCDGPTDRVK
  EGHSPPDDVDIVIKLDNTASTVKAIAIVIPCILALCLLVLVYTVFQFKRKGTPRHILYCK
  RSMQEWV
• Function: Endopeptidase that degrades various components of the extracellular matrix, such as collagen type III and fibronectin. Activates progelatinase A. Involved in the matrix remodeling of blood vessels. Isoform short cleaves fibronectin and also collagen type III, but at lower rate. It has no effect on type I, II, IV and V collagen. However, upon interaction with CSPG4, it may be involved in degradation and invasion of type I collagen by melanoma cells.
• Tissue Specificity: Expressed in heart, brain, placenta, ovary and small intestine. Isoform Short is found in the ovary.
• KEGG Pathway:
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  MicroR.s in cancer (hsa05206)
• Reactome Pathway: Activation of Matrix Metalloproteinases (R-HSA-1592389)

Molecular Interaction Atlas (MIA) of This DOT

20 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 Matrix metalloproteinase-16 (MMP16).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Matrix metalloproteinase-16 (MMP16).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Matrix metalloproteinase-16 (MMP16).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Matrix metalloproteinase-16 (MMP16).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Matrix metalloproteinase-16 (MMP16).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Matrix metalloproteinase-16 (MMP16).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Matrix metalloproteinase-16 (MMP16).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Matrix metalloproteinase-16 (MMP16).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Matrix metalloproteinase-16 (MMP16).	[9]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Matrix metalloproteinase-16 (MMP16).	[10]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Matrix metalloproteinase-16 (MMP16).	[11]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Matrix metalloproteinase-16 (MMP16).	[12]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Matrix metalloproteinase-16 (MMP16).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Matrix metalloproteinase-16 (MMP16).	[14]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Matrix metalloproteinase-16 (MMP16).	[15]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Matrix metalloproteinase-16 (MMP16).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Matrix metalloproteinase-16 (MMP16).	[19]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone decreases the expression of Matrix metalloproteinase-16 (MMP16).	[20]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Matrix metalloproteinase-16 (MMP16).	[20]
MMI270	DM38N2K	Investigative	MMI270 affects the activity of Matrix metalloproteinase-16 (MMP16).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Matrix metalloproteinase-16 (MMP16).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Matrix metalloproteinase-16 (MMP16).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Matrix metalloproteinase-16 (MMP16).	[18]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [3] Up-regulated gene expression of angiogenesis factors in post-chemotherapeutic lung cancer tissues determined by cDNA macroarray. Oncol Rep. 2002 Jul-Aug;9(4):723-8.
• [4] 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.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [7] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [8] 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.
• [9] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [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] The impact of luteal phase support on gene expression of extracellular matrix protein and adhesion molecules in the human endometrium during the window of implantation following controlled ovarian stimulation with a GnRH antagonist protocol. Fertil Steril. 2010 Nov;94(6):2264-71. doi: 10.1016/j.fertnstert.2010.01.068. Epub 2010 Mar 12.
• [12] Marked regression of liver metastasis by combined therapy of ultrasound-mediated NF kappaB-decoy transfer and transportal injection of paclitaxel, in mouse. Int J Cancer. 2008 Apr 1;122(7):1645-56. doi: 10.1002/ijc.23280.
• [13] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [20] Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene. 2006 Nov 23;25(55):7311-23.
• [21] Novel 1-hydroxypiperazine-2,6-diones as new leads in the inhibition of metalloproteinases. J Med Chem. 2011 Dec 22;54(24):8289-98. doi: 10.1021/jm200593b. Epub 2011 Nov 17.