Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTJ4QE7)

• DTT Name: Matrix metalloproteinase-14 (MMP-14)
• Synonyms: Membrane-type-1 matrix metalloproteinase; Membrane-type matrix metalloproteinase 1; MTMMP1; MT1MMP; MT1-MMP; MT-MMP 1; MMP-X1
• Gene Name: MMP14
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Peptidase
• UniProt ID: MMP14_HUMAN
• TTD ID: T65019
• EC Number: EC 3.4.24.80
• Sequence:
  MSPAPRPPRCLLLPLLTLGTALASLGSAQSSSFSPEAWLQQYGYLPPGDLRTHTQRSPQS
  LSAAIAAMQKFYGLQVTGKADADTMKAMRRPRCGVPDKFGAEIKANVRRKRYAIQGLKWQ
  HNEITFCIQNYTPKVGEYATYEAIRKAFRVWESATPLRFREVPYAYIREGHEKQADIMIF
  FAEGFHGDSTPFDGEGGFLAHAYFPGPNIGGDTHFDSAEPWTVRNEDLNGNDIFLVAVHE
  LGHALGLEHSSDPSAIMAPFYQWMDTENFVLPDDDRRGIQQLYGGESGFPTKMPPQPRTT
  SRPSVPDKPKNPTYGPNICDGNFDTVAMLRGEMFVFKERWFWRVRNNQVMDGYPMPIGQF
  WRGLPASINTAYERKDGKFVFFKGDKHWVFDEASLEPGYPKHIKELGRGLPTDKIDAALF
  WMPNGKTYFFRGNKYYRFNEELRAVDSEYPKNIKVWEGIPESPRGSFMGSDEVFTYFYKG
  NKYWKFNNQKLKVEPGYPKSALRDWMGCPSGGRPDEGTEEETEVIIIEVDEEGGGAVSAA
  AVVLPVLLLLLVLAVGLAVFFFRRHGTPRRLLYCQRSLLDKV
• Function: 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. Endopeptidase that degrades various components of the extracellular matrix such as collagen.
• KEGG Pathway:
  TNF signaling pathway (hsa04668)
  GnRH signaling pathway (hsa04912)
• 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-MON

Molecular Interaction Atlas (MIA) of This DTT

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Epigallocatechin gallate	DMCGWBJ	Hepatic fibrosis	DB93.0	Phase 3	[1]
BT1718	DMTXBUV	Solid tumour/cancer	2A00-2F9Z	Phase 1/2a	[2]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GM6001	DM7V9CT	Corneal ulcer	9A76	Discontinued in Phase 2	[3]

12 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-(4-bromophenylsulfonamido)-N-hydroxyacetamide	DMY5STK	Discovery agent	N.A.	Investigative	[4]
2-(biphenyl-4-ylsulfonamido)-N-hydroxyacetamide	DM3PWK7	Discovery agent	N.A.	Investigative	[4]
2-(Biphenyl-4-ylsulfonyl)N-hydroxybenzamide	DMCNV5J	Discovery agent	N.A.	Investigative	[5]
DX-2400	DMF9M06	Solid tumour/cancer	2A00-2F9Z	Investigative	[6]
IK-862	DMJA4UE	Discovery agent	N.A.	Investigative	[7]
MMI270	DM38N2K	Discovery agent	N.A.	Investigative	[8]
N-hydroxy-2-(4-methoxyphenylsulfonamido)acetamide	DM50NKS	Discovery agent	N.A.	Investigative	[4]
N-Hydroxy-2-(4-phenoxy-benzenesulfonyl)benzamide	DM4VADN	Discovery agent	N.A.	Investigative	[5]
PMID23631440C29e	DMM92IB	Discovery agent	N.A.	Investigative	[9]
SR-973	DMU48OD	Discovery agent	N.A.	Investigative	[10]
UK-356618	DM02FGH	Discovery agent	N.A.	Investigative	[11]
[2-(Biphenyl-4-sulfonyl)phenyl]acetic Acid	DM37C25	Discovery agent	N.A.	Investigative	[5]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Prostate cancer	2C82	Prostate	1.22E-07	-0.66	-1.51
Sarcoma	2C82	Muscle tissue	5.90E-132	1.46	4.78
Lung cancer	2C82	Lung tissue	4.39E-36	0.65	1.31

References

• [1] Regioselective synthesis of methylated epigallocatechin gallate via nitrobenzenesulfonyl (Ns) protecting group. Bioorg Med Chem Lett. 2009 Aug 1;19(15):4171-4.
• [2] ClinicalTrials.gov (NCT03486730) BT1718 in Patients With Advanced Solid Tumours.. U.S. National Institutes of Health.
• [3] Introduction of the 4-(4-bromophenyl)benzenesulfonyl group to hydrazide analogs of Ilomastat leads to potent gelatinase B (MMP-9) inhibitors with i... Bioorg Med Chem. 2008 Sep 15;16(18):8745-59.
• [4] Potent arylsulfonamide inhibitors of tumor necrosis factor-alpha converting enzyme able to reduce activated leukocyte cell adhesion molecule sheddi... J Med Chem. 2010 Mar 25;53(6):2622-35.
• [5] Design, synthesis, biological evaluation, and NMR studies of a new series of arylsulfones as selective and potent matrix metalloproteinase-12 inhib... J Med Chem. 2009 Oct 22;52(20):6347-61.
• [6] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1638).
• [7] Discovery of gamma-lactam hydroxamic acids as selective inhibitors of tumor necrosis factor alpha converting enzyme: design, synthesis, and structu... J Med Chem. 2002 Nov 7;45(23):4954-7.
• [8] Methotrexate gamma-hydroxamate derivatives as potential dual target antitumor drugs. Bioorg Med Chem. 2007 Feb 1;15(3):1266-74.
• [9] Matrix metalloproteinase inhibitors based on the 3-mercaptopyrrolidine core. J Med Chem. 2013 Jun 13;56(11):4357-73.
• [10] Synthesis and evaluation of succinoyl-caprolactam gamma-secretase inhibitors. Bioorg Med Chem Lett. 2006 May 1;16(9):2357-63.
• [11] A potent, selective inhibitor of matrix metalloproteinase-3 for the topical treatment of chronic dermal ulcers. J Med Chem. 2003 Jul 31;46(16):3514-25.