Target Validation Information
Target ID T68251
Target Name 72 kDa type IV collagenase
Target Type
Successful
Drug Potency against Target Tanomastat Drug Info Ki = 11 nM [552207]
UK-356618 Drug Info IC50 = 1790 nM [526680]
N-hydroxy-3-(6-methoxy-2-oxo-2H-chromen-3-yl) Drug Info IC50 = 590 nM [529102]
N-Hydroxy-2-(4-phenoxy-benzenesulfonyl)benzamide Drug Info IC50 = 1200 nM [530402]
PNU-107859 Drug Info Ki = 3000 nM [527091]
(+/-)5-(biphenyl-4-yl)-3-hydroxypentanoic acid Drug Info IC50 = 4520 nM [530333]
BB-3644 Drug Info IC50 = 80 nM [552497]
2-(4'-chloro-biphenyl-4-sulfonyl)-pentanoic acid Drug Info IC50 = 792 nM [528153]
5-Biphenyl-4-yl-5-ethyl-pyrimidine-2,4,6-trione Drug Info IC50 = 898 nM [526040]
SR-973 Drug Info Ki = 7 nM [528025]
IK-682 Drug Info Ki = 2050 nM [526446]
Ro-37-9790 Drug Info IC50 = 4.9 nM
L-696418 Drug Info Ki = 200 nM
CIPEMASTAT Drug Info Ki = 154 nM [525693]
Marimastat Drug Info Ki = 6 nM [552892]
ILOMASTAT Drug Info IC50 = 0.4 nM [529683]
BMS 275291 Drug Info IC50 = 39 nM [552278]
Cis-2-aminocyclohexylcarbamoylphosphonic acid Drug Info IC50 = 4000 nM [529297]
3-(4-Phenylethynylbenzoyl)nonanoic acid Drug Info IC50 = 1660 nM [527972]
SC-44463 Drug Info IC50 = 6 nM [526680]
RS-130830 Drug Info Ki = 0.22 nM [527412]
5-Hexyl-5-phenyl-pyrimidine-2,4,6-trione Drug Info IC50 = 1300 nM [526040]
4-(4-(dec-1-ynyl)phenyl)-4-oxobutanoic acid Drug Info IC50 = 3070 nM [527972]
N-hydroxy-3-(2-oxo-2H-chromen-3-yl)propanamide Drug Info IC50 = 200 nM [529102]
Clinopodic acid C Drug Info IC50 = 3260 nM [530340]
5-(4-Phenoxy-phenyl)-pyrimidine-2,4,6-trione Drug Info IC50 = 9000 nM [526040]
5-Biphenyl-4-yl-5-hexyl-pyrimidine-2,4,6-trione Drug Info IC50 = 868 nM [526040]
PD-169469 Drug Info IC50 = 4 nM [527998]
[2-(Biphenyl-4-sulfonyl)phenyl]acetic Acid Drug Info IC50 = 510 nM [530402]
Lithospermic acid Drug Info IC50 = 10200 nM [530340]
BB-1101 Drug Info IC50 = 1.8 nM [534793]
2-(Biphenyl-4-ylsulfonyl)N-hydroxybenzamide Drug Info IC50 = 1300 nM [530402]
EPIGALOCATECHIN GALLATE Drug Info IC50 = 9600 nM [530210]
PG-530742 Drug Info Complete Inhibition = 150 ng/mL [536172]
CIPEMASTAT Drug Info IC50 = 7 nM
MMI270 Drug Info IC50 = 15 nM [525533]
3-(4-(2-phenylethynyl)benzoyl)pentanoic acid Drug Info IC50 = 440 nM [527972]
Action against Disease Model Neovastat Neovastat has a marked inhibitory effect on the formation of blood vessels in the chicken embryo vascularization assay (EVT) and endothelial cell proliferation. In vivo experiments showed that oral administration of Neovastat blocks the formation of blood vessels in Matrigel implants containing basic fibroblast growth factor (bFGF). The antiangiogenic activity of Neovastat was found to be associated with two mechanisms of action. In addition to the inhibition of the matrix metalloproteinase activities (MMP-2, MMP-9, and MMP-12), Neovastat inhibits vascular endothelial growth factor (VEGF) binding to endothelial cells, VEGF-dependent tyrosine phosphorylation, and VEGF-induced vascular permeability in mice. Neovastat was also found to have a significant antit uMor activity. Oral administration of Neovastat in mice with subcutaneous grafted breast cancer (DA3) cells showed a significant reduction in t uMor vol uMe. Neovastat also decreased the n uMber of lung metastases in the Lewis lung carcinoma model. [535315] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations Increased allergen-induced asphyxiation, reduced intral uMinal leukocytes; Increased dextran-sulphate-induced colitis; Protection and reduced hepatocyte apoptosis and necrosis in TNF-induced hepatitis; Increased immune-complex-induced arthritis; Reduced functional recovery from spinal-cord injury; Reduced EAE development [552207]
References
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Ref 526680J 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 529102Bioorg 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 530402J 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 527091J 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.
Ref 530333Bioorg 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 552497Recent developments in the design of specific Matrix Metalloproteinase inhibitors aided by structural and computational studies. Curr Pharm Des. 2005;11(3):295-322.
Ref 528153Bioorg 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 526040Bioorg Med Chem Lett. 2001 Apr 23;11(8):969-72.Novel 5,5-disubstitutedpyrimidine-2,4,6-triones as selective MMP inhibitors.
Ref 528025Bioorg Med Chem Lett. 2006 May 1;16(9):2357-63. Epub 2006 Feb 10.Synthesis and evaluation of succinoyl-caprolactam gamma-secretase inhibitors.
Ref 526446J 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 525693J Med Chem. 2000 Feb 10;43(3):305-41.Protease inhibitors: current status and future prospects.
Ref 552892BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discov. 2008 Dec;7(12):989-1000. doi: 10.1038/nrd2658.
Ref 529683Bioorg 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.
Ref 552278Inhibition of angiogenesis and metastasis in two murine models by the matrix metalloproteinase inhibitor, BMS-275291. Cancer Res. 2001 Dec 1;61(23):8480-5.
Ref 529297J 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.
Ref 527972J 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 526680J 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 527412Bioorg Med Chem Lett. 2005 Feb 15;15(4):1101-6.Structure-based design of potent and selective inhibitors of collagenase-3 (MMP-13).
Ref 526040Bioorg Med Chem Lett. 2001 Apr 23;11(8):969-72.Novel 5,5-disubstitutedpyrimidine-2,4,6-triones as selective MMP inhibitors.
Ref 527972J 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 529102Bioorg 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 530340J Nat Prod. 2009 Aug;72(8):1379-84.Matrix metalloproteinase-2 inhibitors from Clinopodium chinense var. parviflorum.
Ref 526040Bioorg Med Chem Lett. 2001 Apr 23;11(8):969-72.Novel 5,5-disubstitutedpyrimidine-2,4,6-triones as selective MMP inhibitors.
Ref 526040Bioorg Med Chem Lett. 2001 Apr 23;11(8):969-72.Novel 5,5-disubstitutedpyrimidine-2,4,6-triones as selective MMP inhibitors.
Ref 527998J Med Chem. 2006 Feb 9;49(3):923-31.Structural insight into the stereoselective inhibition of MMP-8 by enantiomeric sulfonamide phosphonates.
Ref 530402J 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 530340J Nat Prod. 2009 Aug;72(8):1379-84.Matrix metalloproteinase-2 inhibitors from Clinopodium chinense var. parviflorum.
Ref 535315Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials. Semin Oncol. 2001 Dec;28(6):620-5.
Ref 534793Bioorg 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 530402J 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 530210Bioorg Med Chem Lett. 2009 Aug 1;19(15):4171-4. Epub 2009 Jun 2.Regioselective synthesis of methylated epigallocatechin gallate via nitrobenzenesulfonyl (Ns) protecting group.
Ref 536172Selective 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 525533Bioorg 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 527972J 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.

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