Target Information

Target General Infomation
Target ID
T34296
Former ID
TTDC00150
Target Name
Collagenase 3
Gene Name
MMP13
Synonyms
Collagenase-3; MMP-13; Matrix metalloproteinase 13; Matrix metalloproteinase-13; MMP13
Target Type
Clinical Trial
Disease Cancer [ICD9: 140-229; ICD10: C00-C96]
HCV infection [ICD9: 070.4, 070.5, 070.70; ICD10: B17.1, B18.2]
Inflammatory disease [ICD9: 140-229, 147, 173, 573.3, 710-719; ICD10: C11, C44, K75.9, M00-M25]
Osteoarthritis [ICD9: 715; ICD10: M15-M19, M47]
Pain [ICD9: 338, 356.0, 356.8,780; ICD10: G64, G90.0, R52, G89]
Rheumatoid arthritis [ICD9: 710-719, 714; ICD10: M05-M06]
Function
Plays a role in the degradation of extracellular matrix proteins including fibrillar collagen, fibronectin, TNC and ACAN. Cleaves triple helical collagens, including type I, type II and type III collagen, but has the highest activity with soluble type II collagen. Can also degrade collagen type IV, type XIV and type X. May also function by activating or degrading key regulatory proteins, such as TGFB1 and CTGF. Plays a role in wound healing, tissue remodeling, cartilage degradation, bone development, bone mineralization and ossification. Required for normal embryonic bone development and ossification. Plays a role in the healing of bone fractures via endochondral ossification. Plays a role in wound healing, probably by a mechanism that involves proteolytic activation of TGFB1 and degradation of CTGF. Plays a role in keratinocyte migration during wound healing. May play a role in cell migration and in tumor cell invasion.
BioChemical Class
Peptidase
Target Validation
T34296
UniProt ID
P45452
EC Number
EC 3.4.24.-
Sequence
MHPGVLAAFLFLSWTHCRALPLPSGGDEDDLSEEDLQFAERYLRSYYHPTNLAGILKENA
ASSMTERLREMQSFFGLEVTGKLDDNTLDVMKKPRCGVPDVGEYNVFPRTLKWSKMNLTY
RIVNYTPDMTHSEVEKAFKKAFKVWSDVTPLNFTRLHDGIADIMISFGIKEHGDFYPFDG
PSGLLAHAFPPGPNYGGDAHFDDDETWTSSSKGYNLFLVAAHEFGHSLGLDHSKDPGALM
FPIYTYTGKSHFMLPDDDVQGIQSLYGPGDEDPNPKHPKTPDKCDPSLSLDAITSLRGET
MIFKDRFFWRLHPQQVDAELFLTKSFWPELPNRIDAAYEHPSHDLIFIFRGRKFWALNGY
DILEGYPKKISELGLPKEVKKISAAVHFEDTGKTLLFSGNQVWRYDDTNHIMDKDYPRLI
EEDFPGIGDKVDAVYEKNGYIYFFNGPIQFEYSIWSNRIVRVMPANSILWC
Drugs and Mode of Action
Drug(s) Curcumin Drug Info Phase 3 Cancer [1], [2]
Apratastat Drug Info Phase 2 Rheumatoid arthritis [3], [4]
compound 1 Drug Info Clinical trial Pain [5], [6]
ILOMASTAT Drug Info Preclinical Discovery agent [7], [8]
RS-130830 Drug Info Discontinued in Phase 2 HCV infection [9]
Inhibitor (+/-)5-(biphenyl-4-yl)-3-hydroxypentanoic acid Drug Info [10]
1-(4-Methoxy-benzenesulfonyl)-heptane-3-thiol Drug Info [11]
1-Methyloxy-4-Sulfone-Benzene Drug Info [12]
2-(2-(biphenyl-4-yl)ethylsulfonyl)acetic acid Drug Info [10]
2-(4-methoxybenzylthio)-6-methylpyrimidin-4-ol Drug Info [13]
2-(biphenyl-4-ylsulfonamido)pentanedioic acid Drug Info [13]
2-(Biphenyl-4-ylsulfonyl)N-hydroxybenzamide Drug Info [14]
3-(4-Methoxy-benzenesulfonyl)-cyclohexanethiol Drug Info [15]
3-(4-Methoxy-benzenesulfonyl)-cyclopentanethiol Drug Info [15]
3-(4-Methoxy-benzenesulfonyl)-hexane-1-thiol Drug Info [11]
3-(4-Methoxy-benzenesulfonyl)-pentane-1-thiol Drug Info [11]
3-(4-Methoxy-benzenesulfonyl)-propane-1-thiol Drug Info [11]
3-(4-Phenoxy-benzenesulfonyl)-cyclohexanethiol Drug Info [15]
3-(4-Phenoxy-benzenesulfonyl)-propane-1-thiol Drug Info [11]
3-Benzenesulfonyl-heptanoic acid hydroxyamide Drug Info [16]
3-Cyclohexanesulfonyl-heptanoic acid hydroxyamide Drug Info [16]
3-Methylpyridine Drug Info [12]
4-(2,2'-bithiophen-5-ylmethyleneamino)phenol Drug Info [17]
4-(4-Methoxy-benzenesulfonyl)-butane-2-thiol Drug Info [11]
4-(methyl(4-phenylthiazol-2-yl)amino)phenol Drug Info [17]
4-amino-3-(4-(hexyloxy)phenyl)-4-oxobutanoic acid Drug Info [13]
5-(4'-cyanobiphenyl-4-yl)-3-hydroxypentanoic acid Drug Info [10]
CL82198 Drug Info [18]
compound 1 Drug Info [5]
compound 15 Drug Info [19]
Curcumin Drug Info [17]
Ethyl 2-cyano-2-(quinoxalin-2(1H)-ylidene)acetate Drug Info [17]
Hydroxyaminovaline Drug Info [12]
IK-682 Drug Info [20]
ILOMASTAT Drug Info [21]
MMI270 Drug Info [22]
MMP-13 inhibitors Drug Info [23], [24]
MMP-13 inhibitors Drug Info [23], [24]
N-Hydroxy-2-(4-phenoxy-benzenesulfonyl)benzamide Drug Info [14]
N1,N3-bis(3-methoxybenzyl)isophthalamide Drug Info [25]
N4,N6-dibenzylpyrimidine-4,6-dicarboxamide Drug Info [26]
PD-156 Drug Info [23], [24]
PKF-242-484 Drug Info [27]
Ro-37-9790 Drug Info [28]
RS-130830 Drug Info [29]
SL422 Drug Info [30]
SR-973 Drug Info [31]
TMI-05 Drug Info [32]
UK-356618 Drug Info [33]
WAY-151693 Drug Info [12]
WAY170523 Drug Info [18]
[2-(Biphenyl-4-sulfonyl)phenyl]acetic Acid Drug Info [14]
Modulator Apratastat Drug Info [34], [35]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
NetPath Pathway IL1 Signaling Pathway
PANTHER Pathway Alzheimer disease-presenilin pathway
Plasminogen activating cascade
Pathway Interaction Database Urokinase-type plasminogen activator (uPA) and uPAR-mediated signaling
Reactome Collagen degradation
Degradation of the extracellular matrix
Activation of Matrix Metalloproteinases
Assembly of collagen fibrils and other multimeric structures
WikiPathways Endochondral Ossification
Activation of Matrix Metalloproteinases
Oncostatin M Signaling Pathway
AGE/RAGE pathway
Matrix Metalloproteinases
References
REF 1Nanocurcumin: a promising therapeutic advancement over native curcumin. Crit Rev Ther Drug Carrier Syst. 2013;30(4):331-68.
REF 2(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: 7000).
REF 3ClinicalTrials.gov (NCT00095342) Study Evaluating TMI-005 in Active Rheumatoid Arthritis. U.S. National Institutes of Health.
REF 4(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: 6482).
REF 5Potent, selective spiropyrrolidine pyrimidinetrione inhibitors of MMP-13. Bioorg Med Chem Lett. 2007 Dec 1;17(23):6529-34. Epub 2007 Sep 29.
REF 6(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: 6526).
REF 7(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: 7409).
REF 8Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001387)
REF 9Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010620)
REF 10Bioorg Med Chem Lett. 2009 Oct 1;19(19):5760-3. Epub 2009 Aug 6.The identification of beta-hydroxy carboxylic acids as selective MMP-12 inhibitors.
REF 11Bioorg Med Chem Lett. 1999 Apr 5;9(7):943-8.Discovery of a novel series of selective MMP inhibitors: identification of the gamma-sulfone-thiols.
REF 12How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
REF 13Bioorg Med Chem. 2009 Feb 1;17(3):1101-8. Epub 2008 Mar 8.Ranking the selectivity of PubChem screening hits by activity-based protein profiling: MMP13 as a case study.
REF 14J Med Chem. 2009 Oct 22;52(20):6347-61.Design, synthesis, biological evaluation, and NMR studies of a new series of arylsulfones as selective and potent matrix metalloproteinase-12 inhibitors.
REF 15Bioorg Med Chem Lett. 1999 Jul 5;9(13):1757-60.Synthesis and identification of conformationally constrained selective MMP inhibitors.
REF 16J Med Chem. 2000 Jun 15;43(12):2324-31.Hydroxamic acid derivatives as potent peptide deformylase inhibitors and antibacterial agents.
REF 17Bioorg Med Chem. 2009 Feb 1;17(3):990-1005. Epub 2008 Mar 6.High throughput screening of potentially selective MMP-13 exosite inhibitors utilizing a triple-helical FRET substrate.
REF 18(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: 1637).
REF 19Fragment-based discovery of indole inhibitors of matrix metalloproteinase-13. J Med Chem. 2011 Dec 8;54(23):8174-87.
REF 20J Med Chem. 2002 Nov 7;45(23):4954-7.Discovery of gamma-lactam hydroxamic acids as selective inhibitors of tumor necrosis factor alpha converting enzyme: design, synthesis, and structure-activity relationships.
REF 21J Biol Chem. 2007 Sep 21;282(38):27781-91. Epub 2007 Jul 10.Discovery and characterization of a novel inhibitor of matrix metalloprotease-13 that reduces cartilage damage in vivo without joint fibroplasia side effects.
REF 22Bioorg Med Chem Lett. 2001 Apr 23;11(8):1009-13.Heterocycle-based MMP inhibitors with P2' substituents.
REF 23Effects of selective matrix metalloproteinase inhibitor (PG-116800) to prevent ventricular remodeling after myocardial infarction: results of the PREMIER (Prevention of Myocardial Infarction Early Remodeling) trial. J Am Coll Cardiol. 2006 Jul 4;48(1):15-20. Epub 2006 Jun 21.
REF 24Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure. Am J Physiol Heart Circ Physiol. 2006 Jun;290(6):H2522-7. Epub 2006 Jan 20.
REF 25Bioorg Med Chem Lett. 2010 Jan 15;20(2):576-80. Epub 2009 Nov 22.Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis.
REF 26Bioorg Med Chem Lett. 2009 Jan 1;19(1):47-50. Epub 2008 Nov 18.Calculation of binding free energies for non-zinc chelating pyrimidine dicarboxamide inhibitors with MMP-13.
REF 27Bioorg Med Chem Lett. 2006 May 15;16(10):2632-6. Epub 2006 Mar 3.A cassette-dosing approach for improvement of oral bioavailability of dual TACE/MMP inhibitors.
REF 2811,21-Bisphenyl-19-norpregnane derivatives are selective antiglucocorticoids, Bioorg. Med. Chem. Lett. 7(17):2299-2302 (1997).
REF 29Bioorg Med Chem Lett. 2005 Feb 15;15(4):1101-6.Structure-based design of potent and selective inhibitors of collagenase-3 (MMP-13).
REF 30Design, synthesis, and structure-activity relationships of macrocyclic hydroxamic acids that inhibit tumor necrosis factor alpha release in vitro and in vivo. J Med Chem. 2001 Aug 2;44(16):2636-60.
REF 31Bioorg Med Chem Lett. 2006 May 1;16(9):2357-63. Epub 2006 Feb 10.Synthesis and evaluation of succinoyl-caprolactam gamma-secretase inhibitors.
REF 32Bioorg Med Chem Lett. 2006 Mar 15;16(6):1605-9. Epub 2006 Jan 19.Acetylenic TACE inhibitors. Part 3: Thiomorpholine sulfonamide hydroxamates.
REF 33J Med Chem. 2003 Jul 31;46(16):3514-25.A potent, selective inhibitor of matrix metalloproteinase-3 for the topical treatment of chronic dermal ulcers.
REF 34Drug evaluation: apratastat, a novel TACE/MMP inhibitor for rheumatoid arthritis. Curr Opin Investig Drugs. 2006 Nov;7(11):1014-9.
REF 35Drug insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis. Nat Clin Pract Rheumatol. 2008 Jun;4(6):300-9. Epub 2008 Apr 15.

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