Target Information
| Target General Information | Top | |||||
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| Target ID |
T65019
(Former ID: TTDC00042)
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| Target Name |
Matrix metalloproteinase-14 (MMP-14)
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| Synonyms |
Membrane-type-1 matrix metalloproteinase; Membrane-type matrix metalloproteinase 1; MTMMP1; MT1MMP; MT1-MMP; MT-MMP 1; MMP-X1
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| Gene Name |
MMP14
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Hepatic fibrosis/cirrhosis [ICD-11: DB93] | |||||
| 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.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.24.80
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| Sequence |
MSPAPRPPRCLLLPLLTLGTALASLGSAQSSSFSPEAWLQQYGYLPPGDLRTHTQRSPQS
LSAAIAAMQKFYGLQVTGKADADTMKAMRRPRCGVPDKFGAEIKANVRRKRYAIQGLKWQ HNEITFCIQNYTPKVGEYATYEAIRKAFRVWESATPLRFREVPYAYIREGHEKQADIMIF FAEGFHGDSTPFDGEGGFLAHAYFPGPNIGGDTHFDSAEPWTVRNEDLNGNDIFLVAVHE LGHALGLEHSSDPSAIMAPFYQWMDTENFVLPDDDRRGIQQLYGGESGFPTKMPPQPRTT SRPSVPDKPKNPTYGPNICDGNFDTVAMLRGEMFVFKERWFWRVRNNQVMDGYPMPIGQF WRGLPASINTAYERKDGKFVFFKGDKHWVFDEASLEPGYPKHIKELGRGLPTDKIDAALF WMPNGKTYFFRGNKYYRFNEELRAVDSEYPKNIKVWEGIPESPRGSFMGSDEVFTYFYKG NKYWKFNNQKLKVEPGYPKSALRDWMGCPSGGRPDEGTEEETEVIIIEVDEEGGGAVSAA AVVLPVLLLLLVLAVGLAVFFFRRHGTPRRLLYCQRSLLDKV Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| ADReCS ID | BADD_A00976 | |||||
| HIT2.0 ID | T75IW3 | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | Epigallocatechin gallate | Drug Info | Phase 3 | Hepatic fibrosis | [2], [3], [4], [5] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | GM6001 | Drug Info | Discontinued in Phase 2 | Corneal ulcer | [7] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 12 Inhibitor drugs | + | ||||
| 1 | Epigallocatechin gallate | Drug Info | [1] | |||
| 2 | GM6001 | Drug Info | [8] | |||
| 3 | 2-(4-bromophenylsulfonamido)-N-hydroxyacetamide | Drug Info | [9] | |||
| 4 | 2-(biphenyl-4-ylsulfonamido)-N-hydroxyacetamide | Drug Info | [9] | |||
| 5 | 2-(Biphenyl-4-ylsulfonyl)N-hydroxybenzamide | Drug Info | [10] | |||
| 6 | DX-2400 | Drug Info | [11] | |||
| 7 | MMI270 | Drug Info | [12] | |||
| 8 | N-Hydroxy-2-(4-phenoxy-benzenesulfonyl)benzamide | Drug Info | [10] | |||
| 9 | PMID23631440C29e | Drug Info | [13] | |||
| 10 | SR-973 | Drug Info | [14] | |||
| 11 | UK-356618 | Drug Info | [15] | |||
| 12 | [2-(Biphenyl-4-sulfonyl)phenyl]acetic Acid | Drug Info | [10] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: 1,2-Dimyristoyl-sn-glycero-3-phosphocholine | Ligand Info | |||||
| Structure Description | MT1-MMP HPX Domain with Blade 2 Loop Bound to Nanodiscs | PDB:6CM1 | ||||
| Method | Solution NMR | Resolution | N.A. | Mutation | No | [16] |
| PDB Sequence |
PNICDGNFDT
325 VAMLRGEMFV335 FKERWFWRVR345 NNQVMDGYPM355 PIGQFWRGLP365 ASINTAYERK 375 DGKFVFFKGD385 KHWVFDEASL395 EPGYPKHIKE405 LGRGLPTDKI415 DAALFWMPNG 425 KTYFFRGNKY435 YRFNEELRAV445 DSEYPKNIKV455 WEGIPESPRG465 SFMGSDEVFT 475 YFYKGNKYWK485 FNNQKLKVEP495 GYPKSALRDW505 MGCPSG
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ARG330
3.444
GLY358
2.981
GLN359
1.719
PHE360
1.914
TRP361
2.386
ARG362
1.665
GLY363
4.787
ARG374
2.718
ASP376
4.852
LYS378
2.855
LYS386
3.569
ASP391
4.241
GLU392
2.005
ALA393
2.401
SER394
1.841
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| TNF signaling pathway | hsa04668 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| GnRH signaling pathway | hsa04912 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Parathyroid hormone synthesis, secretion and action | hsa04928 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Degree | 10 | Degree centrality | 1.07E-03 | Betweenness centrality | 5.18E-04 |
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| Closeness centrality | 2.19E-01 | Radiality | 1.39E+01 | Clustering coefficient | 6.67E-02 |
| Neighborhood connectivity | 2.19E+01 | Topological coefficient | 1.22E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | TNF signaling pathway | |||||
| 2 | GnRH signaling pathway | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | Alzheimer disease-presenilin pathway | |||||
| PID Pathway | [+] 2 PID Pathways | + | ||||
| 1 | HIF-2-alpha transcription factor network | |||||
| 2 | Signaling events mediated by focal adhesion kinase | |||||
| Reactome | [+] 3 Reactome Pathways | + | ||||
| 1 | Collagen degradation | |||||
| 2 | Degradation of the extracellular matrix | |||||
| 3 | Activation of Matrix Metalloproteinases | |||||
| WikiPathways | [+] 5 WikiPathways | + | ||||
| 1 | Senescence and Autophagy in Cancer | |||||
| 2 | Activation of Matrix Metalloproteinases | |||||
| 3 | Degradation of collagen | |||||
| 4 | AGE/RAGE pathway | |||||
| 5 | Matrix Metalloproteinases | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Regioselective synthesis of methylated epigallocatechin gallate via nitrobenzenesulfonyl (Ns) protecting group. Bioorg Med Chem Lett. 2009 Aug 1;19(15):4171-4. | |||||
| REF 2 | 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. (Ligand id: 7002). | |||||
| REF 3 | The green tea polyphenol (2)-epigallocatechin-3-gallate (EGCG) is not a beta-secretase inhibitor. Bioorg Med Chem Lett. 2012 Feb 1;22(3):1408-14. | |||||
| REF 4 | Epigallocatechin gallate modulates CYP450 isoforms in the female Swiss-Webster mouse. Toxicol Sci. 2003 Dec;76(2):262-70. | |||||
| REF 5 | Prolyl endopeptidase inhibitors from green tea. Arch Pharm Res. 2001 Aug;24(4):292-6. | |||||
| REF 6 | Anti-ageing pipeline starts to mature.Nat Rev Drug Discov. 2018 Sep;17(9):609-612. | |||||
| REF 7 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001387) | |||||
| REF 8 | 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. | |||||
| REF 9 | 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. | |||||
| REF 10 | 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. | |||||
| REF 11 | 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). | |||||
| REF 12 | Methotrexate gamma-hydroxamate derivatives as potential dual target antitumor drugs. Bioorg Med Chem. 2007 Feb 1;15(3):1266-74. | |||||
| REF 13 | Matrix metalloproteinase inhibitors based on the 3-mercaptopyrrolidine core. J Med Chem. 2013 Jun 13;56(11):4357-73. | |||||
| REF 14 | Synthesis and evaluation of succinoyl-caprolactam gamma-secretase inhibitors. Bioorg Med Chem Lett. 2006 May 1;16(9):2357-63. | |||||
| REF 15 | 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. | |||||
| REF 16 | MT1-MMP Binds Membranes by Opposite Tips of Its beta Propeller to Position It for Pericellular Proteolysis. Structure. 2019 Feb 5;27(2):281-292.e6. | |||||
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