Target Information

Target General Infomation
Target ID
T68251
Former ID
TTDC00104
Target Name
72 kDa type IV collagenase
Gene Name
MMP2
Synonyms
72 kDa gelatinase; Gelatinase A; MMP-2; Matrix metalloproteinase 2; Matrix metalloproteinase-2; TBE-1; MMP2
Target Type
Successful
Disease Acne vulgaris [ICD9: 706.1; ICD10: L70.0]
Brain cancer [ICD9: 191, 225.0; ICD10: C71, D33]
Cancer [ICD9: 140-229; ICD10: C00-C96]
HCV infection [ICD9: 070.4, 070.5, 070.70; ICD10: B17.1, B18.2]
Lung cancer; Prostate cancer [ICD9: 140-229, 162, 185; ICD10: C33-C34, C61]
Multiple scierosis [ICD9: 340; ICD10: G35]
Non-small-cell lung cancer; Hormone-refractory prostate cancer; Kaposi's sarcoma [ICD9: 140-229, 162, 176, 185, 204.0; ICD10: C33, C33-C34, C34, C46, C61, C91.0]
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]
Pancreatic cancer; Lung cancer; Ovarian cancer; Osteoarthritis [ICD9: 140-229, 157, 162, 183, 715; ICD10: C25, C33-C34, C56, M15-M19, M47]
Pancreatic cancer; Lung cancer [ICD9: 140-229, 157, 162; ICD10: C25, C33-C34]
Pancreatic cancer [ICD9: 140-199, 140-229, 157, 210-229; ICD10: C25]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Function
Isoform 2: Mediates the proteolysis of CHUK/IKKA and initiates a primary innate immune response by inducing mitochondrial-nuclear stress signaling with activation of the pro- inflammatory NF-kappaB, NFAT and IRF transcriptional pathways.
BioChemical Class
Peptidase
Target Validation
T68251
UniProt ID
P08253
EC Number
EC 3.4.24.24
Sequence
MEALMARGALTGPLRALCLLGCLLSHAAAAPSPIIKFPGDVAPKTDKELAVQYLNTFYGC
PKESCNLFVLKDTLKKMQKFFGLPQTGDLDQNTIETMRKPRCGNPDVANYNFFPRKPKWD
KNQITYRIIGYTPDLDPETVDDAFARAFQVWSDVTPLRFSRIHDGEADIMINFGRWEHGD
GYPFDGKDGLLAHAFAPGTGVGGDSHFDDDELWTLGEGQVVRVKYGNADGEYCKFPFLFN
GKEYNSCTDTGRSDGFLWCSTTYNFEKDGKYGFCPHEALFTMGGNAEGQPCKFPFRFQGT
SYDSCTTEGRTDGYRWCGTTEDYDRDKKYGFCPETAMSTVGGNSEGAPCVFPFTFLGNKY
ESCTSAGRSDGKMWCATTANYDDDRKWGFCPDQGYSLFLVAAHEFGHAMGLEHSQDPGAL
MAPIYTYTKNFRLSQDDIKGIQELYGASPDIDLGTGPTPTLGPVTPEICKQDIVFDGIAQ
IRGEIFFFKDRFIWRTVTPRDKPMGPLLVATFWPELPEKIDAVYEAPQEEKAVFFAGNEY
WIYSASTLERGYPKPLTSLGLPPDVQRVDAAFNWSKNKKTYIFAGDKFWRYNEVKKKMDP
GFPKLIADAWNAIPDNLDAVVDLQGGGHSYFFKGAYYLKLENQSLKSVKFGSIKSDWLGC
Drugs and Mode of Action
Drug(s) Prinomastat Drug Info Approved Lung cancer; Prostate cancer [1], [2]
Marimastat Drug Info Phase 3 Pancreatic cancer [3], [4]
Metastat Drug Info Phase 1 Acne vulgaris [5], [6]
Neovastat Drug Info Phase 1 Non-small-cell lung cancer; Renal cell carcinoma [7]
ILOMASTAT Drug Info Preclinical Discovery agent [8], [9]
RO-26-2853 Drug Info Preclinical Cancer [10]
BMS 275291 Drug Info Discontinued in Phase 3 Non-small-cell lung cancer; Hormone-refractory prostate cancer; Kaposi's sarcoma [11]
Marimastat Drug Info Discontinued in Phase 3 Pancreatic cancer; Lung cancer [3], [12]
Prinomastat Drug Info Discontinued in Phase 3 Brain cancer [1], [2]
Tanomastat Drug Info Discontinued in Phase 3 Pancreatic cancer; Lung cancer; Ovarian cancer; Osteoarthritis [13], [14]
Galarubicin Drug Info Discontinued in Phase 2 Solid tumours [15]
RS-130830 Drug Info Discontinued in Phase 2 HCV infection [16]
BB-1101 Drug Info Terminated Multiple scierosis [17]
BB-3644 Drug Info Terminated Cancer [18]
CDP-845 Drug Info Terminated Cancer [19]
L-696418 Drug Info Terminated Discovery agent [20]
SC-44463 Drug Info Terminated Discovery agent [21]
Inhibitor (+/-)5-(biphenyl-4-yl)-3-hydroxypentanoic acid Drug Info [22]
2-(4'-chloro-biphenyl-4-sulfonyl)-pentanoic acid Drug Info [23]
2-(Biphenyl-4-ylsulfonyl)N-hydroxybenzamide Drug Info [24]
3-(4-(2-phenylethynyl)benzoyl)pentanoic acid Drug Info [25]
3-(4-Phenylethynylbenzoyl)nonanoic acid Drug Info [25]
4-(4-(dec-1-ynyl)phenyl)-4-oxobutanoic acid Drug Info [25]
5-(4-Phenoxy-phenyl)-pyrimidine-2,4,6-trione Drug Info [26]
5-Biphenyl-4-yl-5-ethyl-pyrimidine-2,4,6-trione Drug Info [26]
5-Biphenyl-4-yl-5-hexyl-pyrimidine-2,4,6-trione Drug Info [26]
5-Hexyl-5-phenyl-pyrimidine-2,4,6-trione Drug Info [26]
BB-1101 Drug Info [27]
BB-3644 Drug Info [28], [18]
BMS 275291 Drug Info [28], [29], [30], [11]
Cis-2-aminocyclohexylcarbamoylphosphonic acid Drug Info [31]
Clinopodic acid C Drug Info [32]
EPIGALOCATECHIN GALLATE Drug Info [33]
Folate gamma-hydroxamic acid Drug Info [34]
Folate gamma-L-proline-hydroxamic acid Drug Info [34]
Galarubicin Drug Info [35]
IK-682 Drug Info [36]
ILOMASTAT Drug Info [37]
L-696418 Drug Info [38]
Lithospermic acid Drug Info [32]
Marimastat Drug Info [28], [39], [40], [41]
Metastat Drug Info [42]
Methotrexate gamma-hydroxamic acid Drug Info [34]
Methotrexate gamma-L-proline-hydroxamic acid Drug Info [34]
MMI270 Drug Info [43]
N-Hydroxy-2-(4-phenoxy-benzenesulfonyl)benzamide Drug Info [24]
N-hydroxy-3-(2-oxo-2H-chromen-3-yl)propanamide Drug Info [44]
N-hydroxy-3-(6-methoxy-2-oxo-2H-chromen-3-yl) Drug Info [44]
Neovastat Drug Info [45], [46], [47]
PD-169469 Drug Info [48]
PNU-107859 Drug Info [49]
Prinomastat Drug Info [28], [50], [51], [52], [53]
RO-26-2853 Drug Info [10]
Ro-37-9790 Drug Info [54]
Roche 28-2653 Drug Info [55]
RS-130830 Drug Info [56]
SC-44463 Drug Info [57]
SC-74020 Drug Info [58]
SR-973 Drug Info [59]
Tanomastat Drug Info [28], [60], [61], [62]
UK-356618 Drug Info [57]
[2-(Biphenyl-4-sulfonyl)phenyl]acetic Acid Drug Info [24]
Modulator CDP-845 Drug Info [63]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Leukocyte transendothelial migration
GnRH signaling pathway
Estrogen signaling pathway
Pathways in cancer
Proteoglycans in cancer
Bladder cancer
NetPath Pathway Leptin Signaling Pathway
TCR Signaling Pathway
ID Signaling Pathway
PANTHER Pathway Alzheimer disease-presenilin pathway
Pathway Interaction Database LPA receptor mediated events
Plasma membrane estrogen receptor signaling
Osteopontin-mediated events
Validated transcriptional targets of AP1 family members Fra1 and Fra2
Angiopoietin receptor Tie2-mediated signaling
Direct p53 effectors
amb2 Integrin signaling
ATF-2 transcription factor network
FOXM1 transcription factor network
Regulation of nuclear beta catenin signaling and target gene transcription
Syndecan-2-mediated signaling events
Reactome Collagen degradation
Degradation of the extracellular matrix
Activation of Matrix Metalloproteinases
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
EPH-ephrin mediated repulsion of cells
WikiPathways Activation of Matrix Metalloproteinases
AGE/RAGE pathway
Matrix Metalloproteinases
References
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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: 5220).
REF 4Randomized phase III trial of marimastat versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy: Eastern Cooperative Oncology Group trial E2196. J Clin Oncol. 2004 Dec 1;22(23):4683-90.
REF 5ClinicalTrials.gov (NCT00001683) A Phase I Study of Oral COL-3 (NSC-683551), a Matrix Metalloproteinase Inhibitor, in Patients With Refractory Metastatic Cancer. U.S. National Institutes of Health.
REF 6A phase I and pharmacokinetic study of Col-3 (Metastat), an oral tetracycline derivative with potent matrix metalloproteinase and antitumor properties. Clin Cancer Res. 2004 Oct 1;10(19):6512-21.
REF 7Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
REF 8(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 9Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001387)
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REF 11Phase 1/2 trial of BMS-275291 in patients with human immunodeficiency virus-related Kaposi sarcoma: a multicenter trial of the AIDS Malignancy Consortium. Cancer. 2008 Mar 1;112(5):1083-8.
REF 12Emerging drugs for the treatment of chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2006 May;11(2):275-91.
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REF 14Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010243)
REF 15Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004410)
REF 16Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010620)
REF 17Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006361)
REF 18A phase I and pharmacological study of the matrix metalloproteinase inhibitor BB-3644 in patients with solid tumours. Br J Cancer. 2004 Feb 23;90(4):800-4.
REF 19Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006498)
REF 20Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006282)
REF 21Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007717)
REF 22Bioorg 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 23Bioorg Med Chem Lett. 2006 Jun 15;16(12):3096-100. Epub 2006 May 2.Synthesis and SAR of alpha-sulfonylcarboxylic acids as potent matrix metalloproteinase inhibitors.
REF 24J 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 25J 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 26Bioorg Med Chem Lett. 2001 Apr 23;11(8):969-72.Novel 5,5-disubstitutedpyrimidine-2,4,6-triones as selective MMP inhibitors.
REF 27Bioorg Med Chem Lett. 1998 Jun 16;8(12):1443-8.Broad spectrum matrix metalloproteinase inhibitors: an examination of succinamide hydroxamate inhibitors with P1 C alpha gem-disubstitution.
REF 28Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer. 2006 Mar;6(3):227-39.
REF 29Randomized phase II feasibility study of combining the matrix metalloproteinase inhibitor BMS-275291 with paclitaxel plus carboplatin in advanced non-small cell lung cancer. Lung Cancer. 2004 Dec;46(3):361-8.
REF 30Randomized phase III study of matrix metalloproteinase inhibitor BMS-275291 in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: National Cancer Institute of Canada-Clinical Trials Group Study BR.18. J Clin Oncol. 2005 Apr 20;23(12):2831-9.
REF 31J Med Chem. 2008 Mar 13;51(5):1406-14. Epub 2008 Feb 8.Carbamoylphosphonate matrix metalloproteinase inhibitors 6: cis-2-aminocyclohexylcarbamoylphosphonic acid, a novel orally active antimetastaticmatrix metalloproteinase-2 selective inhibitor--synthesis and pharmacodynamic and pharmacokinetic analysis.
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REF 36J 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 37Bioorg Med Chem. 2008 Sep 15;16(18):8745-59. Epub 2008 Jul 20.Introduction of the 4-(4-bromophenyl)benzenesulfonyl group to hydrazide analogs of Ilomastat leads to potent gelatinase B (MMP-9) inhibitors with improved selectivity.
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REF 39Metalloelastase (MMP-12) induced inflammatory response in mice airways: effects of dexamethasone, rolipram and marimastat. Eur J Pharmacol. 2007 Mar 15;559(1):75-81. Epub 2006 Dec 12.
REF 40Matrix metalloproteinase-2 involvement in breast cancer progression: a mini-review. Med Sci Monit. 2009 Feb;15(2):RA32-40.
REF 41Matrix metalloproteinase inhibition as a novel anticancer strategy: a review with special focus on batimastat and marimastat. Pharmacol Ther. 1997;75(1):69-75.
REF 42Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nat Rev Cancer. 2002 Sep;2(9):657-72.
REF 43Bioorg Med Chem Lett. 1999 Jun 21;9(12):1691-6.Picking the S1, S1' and S2' pockets of matrix metalloproteinases. A niche for potent acyclic sulfonamide inhibitors.
REF 44Bioorg Med Chem. 2008 Jan 1;16(1):530-5. Epub 2007 Sep 14.Chromen-based TNF-alpha converting enzyme (TACE) inhibitors: design, synthesis, and biological evaluation.
REF 45Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials. Semin Oncol. 2001 Dec;28(6):620-5.
REF 46The effect of Neovastat (AE-941) on an experimental metastatic bone tumor model. Int J Oncol. 2002 Feb;20(2):299-303.
REF 47Neovastat (AE-941) inhibits the airway inflammation and hyperresponsiveness in a murine model of asthma. J Microbiol. 2005 Feb;43(1):11-6.
REF 48J Med Chem. 2006 Feb 9;49(3):923-31.Structural insight into the stereoselective inhibition of MMP-8 by enantiomeric sulfonamide phosphonates.
REF 49J Med Chem. 2004 Jun 3;47(12):3065-74.A molecular basis for the selectivity of thiadiazole urea inhibitors with stromelysin-1 and gelatinase-A from generalized born molecular dynamics simulations.
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REF 52Delayed administration of a matrix metalloproteinase inhibitor limits progressive brain injury after hypoxia-ischemia in the neonatal rat. J Neuroinflammation. 2008 Aug 11;5:34.
REF 53Inhibition of gelatinase activity reduces neural injury in an ex vivo model of hypoxia-ischemia. Neuroscience. 2009 Jun 2;160(4):755-66. Epub 2009 Mar 9.
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REF 55The new synthetic matrix metalloproteinase inhibitor (Roche 28-2653) reduces tumor growth and prolongs survival in a prostate cancer standard rat model. Oncogene. 2002 Mar 27;21(13):2089-96.
REF 56Bioorg Med Chem Lett. 2005 Feb 15;15(4):1101-6.Structure-based design of potent and selective inhibitors of collagenase-3 (MMP-13).
REF 57J 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.
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REF 59Bioorg Med Chem Lett. 2006 May 1;16(9):2357-63. Epub 2006 Feb 10.Synthesis and evaluation of succinoyl-caprolactam gamma-secretase inhibitors.
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