Target Information

Target General Infomation
Target ID
T03500
Former ID
TTDC00157
Target Name
MMP-12
Gene Name
MMP12
Synonyms
HME; ME; MMP-12; Macrophage elastase; Matrix metalloproteinase-12; MMP12
Target Type
Discontinued
Disease Atherosclerosis [ICD9: 414.0, 440; ICD10: I70]
Aortic aneurysm [ICD10: I71]
Asthma; Chronic obstructive pulmonary disease [ICD9: 490-492, 493, 494-496; ICD10: J40-J44, J47, J45]
Asthma [ICD9: 493; ICD10: J45]
Chronic obstructive pulmonary disease [ICD9: 490-492, 494-496; ICD10: J40-J44, J47]
Inflammatory disease [ICD9: 140-229, 147, 173, 573.3, 710-719; ICD10: C11, C44, K75.9, M00-M25]
Non-small-cell lung cancer; Renal cell carcinoma [ICD9: 140-229, 162, 162.9, 189, 204.0; ICD10: C33, C33-C34, C34, C34.90, C64, C91.0]
Function
May be involved in tissue injuryand remodeling. Has significant elastolytic activity. Can accept large and small amino acids at the P1' site, but has a preference for leucine. Aromatic or hydrophobic residues are preferred at the P1 site, with small hydrophobic residues (preferably alanine) occupying P3.
BioChemical Class
Peptidase
Target Validation
T03500
UniProt ID
P39900
EC Number
EC 3.4.24.65
Sequence
MKFLLILLLQATASGALPLNSSTSLEKNNVLFGERYLEKFYGLEINKLPVTKMKYSGNLM
KEKIQEMQHFLGLKVTGQLDTSTLEMMHAPRCGVPDVHHFREMPGGPVWRKHYITYRINN
YTPDMNREDVDYAIRKAFQVWSNVTPLKFSKINTGMADILVVFARGAHGDFHAFDGKGGI
LAHAFGPGSGIGGDAHFDEDEFWTTHSGGTNLFLTAVHEIGHSLGLGHSSDPKAVMFPTY
KYVDINTFRLSADDIRGIQSLYGDPKENQRLPNPDNSEPALCDPNLSFDAVTTVGNKIFF
FKDRFFWLKVSERPKTSVNLISSLWPTLPSGIEAAYEIEARNQVFLFKDDKYWLISNLRP
EPNYPKSIHSFGFPNFVKKIDAAVFNPRFYRTYFFVDNQYWRYDERRQMMDPGYPKLITK
NFQGIGPKIDAVFYSKNKYYYFFQGSNQFEYDFLLQRITKTLKSNSWFGC
Drugs and Mode of Action
Drug(s) FP-025 Drug Info Phase 1 Asthma [1]
Neovastat Drug Info Phase 1 Non-small-cell lung cancer; Renal cell carcinoma [2]
ILOMASTAT Drug Info Preclinical Discovery agent [3], [4]
AZD1236 Drug Info Discontinued in Phase 2 Chronic obstructive pulmonary disease [5], [6]
V85546 Drug Info Discontinued in Phase 1 Inflammatory disease [7]
Inhibitor (+/-)5-(biphenyl-4-yl)-3-hydroxypentanoic acid Drug Info [8]
2-(2-(biphenyl-4-yl)ethylsulfinyl)acetic acid Drug Info [8]
2-(2-(biphenyl-4-yl)ethylsulfonyl)acetic acid Drug Info [8]
2-(2-(biphenyl-4-yl)ethylthio)acetic acid Drug Info [8]
2-(Biphenyl-4-ylsulfonyl)N-hydroxybenzamide Drug Info [9]
3-(4-(2-phenylethynyl)benzoyl)pentanoic acid Drug Info [10]
3-(4-Phenylethynylbenzoyl)nonanoic acid Drug Info [10]
3-Benzenesulfonyl-heptanoic acid hydroxyamide Drug Info [11]
3-Cyclohexanesulfonyl-heptanoic acid hydroxyamide Drug Info [11]
4-(4-(dec-1-ynyl)phenyl)-4-oxobutanoic acid Drug Info [10]
5-(3'-cyanobiphenyl-4-yl)-3-hydroxypentanoic acid Drug Info [8]
5-(4'-cyanobiphenyl-4-yl)-3-hydroxypentanoic acid Drug Info [8]
5-(biphenyl-4-yl)-3-methoxypentanoic acid Drug Info [8]
5-(biphenyl-4-yl)-3-oxopentanoic acid Drug Info [8]
Acetate Ion Drug Info [12]
AGELADINE A Drug Info [13]
AZD1236 Drug Info [14]
compound 1 Drug Info [15]
compound 20 Drug Info [16]
compound 5 Drug Info [15]
CP-271485 Drug Info [12]
FP-025 Drug Info [17]
ILOMASTAT Drug Info [10]
MMP-12 inhibitors Drug Info [18]
MMP-408 Drug Info [18]
N-(biphenyl-4-ylsulfonyl)-D-leucine Drug Info [19]
N-(dibenzo[b,d]thiophen-3-ylsulfonyl)-L-valine Drug Info [19]
N-Hydroxy-2-(4-methoxy-benzenesulfonyl)benzamide Drug Info [9]
N-Hydroxy-2-(4-phenoxy-benzenesulfonyl)benzamide Drug Info [9]
N-oxo-2-(phenylsulfonylamino)ethanamide Drug Info [19]
N-oxo-2-[(4-phenylphenyl)sulfonylamino]ethanamide Drug Info [19]
N-[(4-methoxyphenyl)sulfonyl]-D-alanine Drug Info [19]
Neovastat Drug Info [20], [21], [22]
PF-00356231 Drug Info [23]
PUP-1 Drug Info [18]
RXP-470 Drug Info [18]
RXP470.1 Drug Info [24]
V85546 Drug Info [25]
WAY-644 Drug Info [18]
[2-(Biphenyl-4-sulfonyl)phenyl]acetic Acid Drug Info [9]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
NetPath Pathway IL1 Signaling Pathway
IL5 Signaling Pathway
Pathway Interaction Database Urokinase-type plasminogen activator (uPA) and uPAR-mediated signaling
Reactome Collagen degradation
Degradation of the extracellular matrix
WikiPathways TGF beta Signaling Pathway
Degradation of collagen
Matrix Metalloproteinases
References
REF 1ClinicalTrials.gov (NCT02238834) Phase 1 Safety, Tolerability and Pharmacokinetics (PK) Study of FP-025 in Healthy Volunteers
REF 2Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
REF 3(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 4Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001387)
REF 5(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: 7844).
REF 6Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026714)
REF 7Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020392)
REF 8Bioorg 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 9J 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 10J Med Chem. 2006 Jan 26;49(2):456-8.Selective inhibition of matrix metalloproteinase isozymes and in vivo protection against emphysema by substituted gamma-keto carboxylic acids.
REF 11J Med Chem. 2000 Jun 15;43(12):2324-31.Hydroxamic acid derivatives as potent peptide deformylase inhibitors and antibacterial agents.
REF 12How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
REF 13Bioorg Med Chem Lett. 2009 Sep 15;19(18):5461-3. Epub 2009 Jul 23.Synthesis of novel ageladine A analogs showing more potent matrix metalloproteinase (MMP)-12 inhibitory activity than the natural product.
REF 14Clinical pipeline report, company report or official report of AstraZeneca (2009).
REF 15Target-Activated Prodrugs (TAPs) for the Autoregulated Inhibition of MMP12. ACS Med Chem Lett. 2012 Jul 14;3(8):653-7.
REF 16Discovery of potent and selective matrix metalloprotease 12 inhibitors for the potential treatment of chronic obstructive pulmonary disease (COPD). Bioorg Med Chem Lett. 2012 Jan 1;22(1):138-43.
REF 17Potential clinical implications of recent matrix metalloproteinase inhibitor design strategies.
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: 1636).
REF 19The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
REF 20Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials. Semin Oncol. 2001 Dec;28(6):620-5.
REF 21The effect of Neovastat (AE-941) on an experimental metastatic bone tumor model. Int J Oncol. 2002 Feb;20(2):299-303.
REF 22Neovastat (AE-941) inhibits the airway inflammation and hyperresponsiveness in a murine model of asthma. J Microbiol. 2005 Feb;43(1):11-6.
REF 23DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-4. Nucleic Acids Res. 2011 January
REF 24Molecular determinants of a selective matrix metalloprotease-12 inhibitor: insights from crystallography and thermodynamic studies. J Med Chem. 2013 Feb 14;56(3):1149-59.
REF 25Clinical pipeline report, company report or official report of Vernalis.

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