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Chemical Compound Review

AC1NRBJE     (2R)-N'-hydroxy-N-[(1S)-2- (5H-indol-3-yl)...

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Disease relevance of GM6001

  • Metalloprotease inhibitors GM6001 and TAPI-0 inhibit the obligate intracellular human pathogen Chlamydia trachomatis by targeting peptide deformylase of the bacterium [1].
  • Induced barrier permeability is likely to be Galpha(12/13)-mediated as chelation of Galpha(q)-mediated intracellular calcium with BAPTA-AM, pertussis toxin inhibition of Galpha(i/o), or GM6001 inhibition of matrix metalloproteinase had no effect, whereas Y-27632 inhibition of the Galpha(12/13)-mediated Rho kinase abrogated the response [2].
  • Compared to placebo, GM6001 significantly inhibited intimal hyperplasia and intimal collagen content, and it increased lumen area in stented arteries without effects on proliferation rates [3].
  • RESULTS: In a simulation of intervention therapy, mice were inoculated with breast cancer cells, and at the time of diagnosis of osteolytic lesions, the mice were treated for 10 or 15 consecutive days with BB-94 or GM6001, respectively [4].
  • EXPERIMENTAL DESIGN: In the present study, we tested two general MMP inhibitors, BB-94 and GM6001, in a mouse model of breast cancer-induced bone metastasis [4].

Psychiatry related information on GM6001


High impact information on GM6001

  • Gelatinolytic activity was detected earliest within the matrix of cortical blood vessels and later within neurons and pia arachnoid (> or =3 hours), particularly within piriform cortex; this activity was suppressed by injection of the metalloprotease inhibitor GM6001 or in vitro by the addition of a zinc chelator (1,10-phenanthroline) [6].
  • Addition of exogenous TN-C to SMCs on floating collagen, or to SMCs treated with GM6001, restores the EGF growth response and "rescues" cells from apoptosis [7].
  • Spontaneous and inducible Axl cleavage was inhibited by the broad-spectrum metalloproteinase inhibitor GM6001 and by hydroxamate GW280264X, which is capable of blocking ADAM10 and ADAM17 [8].
  • Overall, at 1 week after balloon angioplasty, GM6001 resulted in a 33% reduction in collagen content in balloon-injured arteries compared with placebo (750 +/- 143 to 500 +/- 78 micrograms hydroxyproline per segment, P < .004), which was associated with a nonsignificant 25% reduction in intimal area [9].
  • Invasion was linked to activation of matrix metalloproteinase (MMP)-mediated degradation of basement membrane in H-2Kd-Ecad-expressing tissue constructs that was blocked by MMP inhibition (GM6001) [10].

Biological context of GM6001


Anatomical context of GM6001

  • The matrix metalloproteinase inhibitor GM6001 also interfered with osteoblast elongation [16].
  • Importantly, co-treatment with two different MMP inhibitors (MMPIs), the broad spectrum inhibitor GM6001 and an MMP-2/9-specific inhibitor, suppressed TGFbeta-induced ASC changes, including the epithelial-mesenchymal transformation of lens epithelial cells [17].
  • In contrast, the murine mature osteocyte cell line, MLO-Y4, was unaffected by GM6001 under all culture conditions [12].
  • In vitro migration of resting T cells across a basal lamina equivalent is mediated by gelatinase B, because it is specifically blocked by GM6001, a hydroxamic acid inhibitor of matrix metalloproteinases [18].
  • Drugs such as PP2 and GM6001, inhibitors of c-src and matrix metalloproteinases (MMPs), respectively, and risedronate were used to determine osteoclast transmigration regulating factors [19].

Associations of GM6001 with other chemical compounds

  • A hydroxamate class inhibitor (GM6001, or Ilomastat) blocked activation of MT1-MMP in MCF7 cells but not in HT1080 cells [20].
  • The MMP inhibitor GM6001 and the AT1 receptor antagonist Losartan inhibited these effects [21].
  • Matrix metalloprotease (MMP) activity was increased in CYP-2C9-overexpressing cells and correlated with increased invasion through Matrigel-coated Transwell chambers: an effect sensitive to the CYP 2C9 inhibitor sulfaphenazole as well as to EEZE and the MMP inhibitor GM6001 [22].
  • The degradation was blocked by the metalloproteinase inhibitors GM6001 and 1, 10-phenantroline (both of which inhibited P. aeruginosa elastase, P. mirabilis proteinase, and E. faecalis gelatinase), or the inhibitor E64 (which inhibited S. pyogenes cysteine proteinase) [23].
  • Both recombinant human TIMP-1 and the synthetic MMP inhibitors, GM6001 and MMP-2-MMP-9 Inhibitor III, suppressed migration of human dermal microvascular endothelial cells (HDMVEC) in a dose-dependent fashion [24].

Gene context of GM6001

  • GM6001, a hydroxamate inhibitor of MMP activity, down-regulated the production of VEGF in U-MT cells to the levels observed in the U-neo control [25].
  • Also, the metalloproteinase inhibitor GM6001 and an anti-BTC neutralizing antibody suppressed the GLP-1 proliferative effect [13].
  • Furthermore, we found that the membrane type MMP, MT1-MMP, which is produced by osteoblasts, could activate latent TGF-beta and that antibodies neutralizing endogenous TGF-beta led to a similar decrease in cell number as GM6001 [12].
  • This shedding was inhibited by the broad range metalloproteinase inhibitor GM6001, the two potent ADAM17 inhibitors GW280264X and TAPI-2, and was absent in mice lacking functional ADAM17 (ADAM17 lacking Zn-binding domain; ADAM17(DeltaZn/DeltaZn)) [26].
  • Both the metalloproteinase inhibitor GM6001 and RNA interference of ADAM10 completely prevented the release of sCD46 and increased the expression of vCD46 on HaCaT cell vesicles, suggesting that ADAM10 releases sCD46 from the apoptotic vesicles [27].

Analytical, diagnostic and therapeutic context of GM6001


  1. Metalloprotease inhibitors GM6001 and TAPI-0 inhibit the obligate intracellular human pathogen Chlamydia trachomatis by targeting peptide deformylase of the bacterium. Balakrishnan, A., Patel, B., Sieber, S.A., Chen, D., Pachikara, N., Zhong, G., Cravatt, B.F., Fan, H. J. Biol. Chem. (2006) [Pubmed]
  2. Functional selectivity of G protein signaling by agonist peptides and thrombin for the protease-activated receptor-1. McLaughlin, J.N., Shen, L., Holinstat, M., Brooks, J.D., Dibenedetto, E., Hamm, H.E. J. Biol. Chem. (2005) [Pubmed]
  3. Arterial repair after stenting and the effects of GM6001, a matrix metalloproteinase inhibitor. Li, C., Cantor, W.J., Nili, N., Robinson, R., Fenkell, L., Tran, Y.L., Whittingham, H.A., Tsui, W., Cheema, A.N., Sparkes, J.D., Pritzker, K., Levy, D.E., Strauss, B.H. J. Am. Coll. Cardiol. (2002) [Pubmed]
  4. Synthetic matrix metalloproteinase inhibitors inhibit growth of established breast cancer osteolytic lesions and prolong survival in mice. Winding, B., NicAmhlaoibh, R., Misander, H., Høegh-Andersen, P., Andersen, T.L., Holst-Hansen, C., Heegaard, A.M., Foged, N.T., Brünner, N., Delaissé, J.M. Clin. Cancer Res. (2002) [Pubmed]
  5. Society of Biomaterials Graduate Degree Candidate Student Research Award. Matrix metalloproteinase inhibitor within an absorbable coating for vascular applications: delivery device characterization and reduction of smooth muscle cell proliferation and migration. Caldwell, R.A., Vyavahare, N., Langan, E.M., LaBerge, M. Journal of biomedical materials research. Part A. (2003) [Pubmed]
  6. Cortical spreading depression activates and upregulates MMP-9. Gursoy-Ozdemir, Y., Qiu, J., Matsuoka, N., Bolay, H., Bermpohl, D., Jin, H., Wang, X., Rosenberg, G.A., Lo, E.H., Moskowitz, M.A. J. Clin. Invest. (2004) [Pubmed]
  7. Regulation of tenascin-C, a vascular smooth muscle cell survival factor that interacts with the alpha v beta 3 integrin to promote epidermal growth factor receptor phosphorylation and growth. Jones, P.L., Crack, J., Rabinovitch, M. J. Cell Biol. (1997) [Pubmed]
  8. Soluble Axl is generated by ADAM10-dependent cleavage and associates with Gas6 in mouse serum. Budagian, V., Bulanova, E., Orinska, Z., Duitman, E., Brandt, K., Ludwig, A., Hartmann, D., Lemke, G., Saftig, P., Bulfone-Paus, S. Mol. Cell. Biol. (2005) [Pubmed]
  9. In vivo collagen turnover following experimental balloon angioplasty injury and the role of matrix metalloproteinases. Strauss, B.H., Robinson, R., Batchelor, W.B., Chisholm, R.J., Ravi, G., Natarajan, M.K., Logan, R.A., Mehta, S.R., Levy, D.E., Ezrin, A.M., Keeley, F.W. Circ. Res. (1996) [Pubmed]
  10. E-cadherin suppression accelerates squamous cell carcinoma progression in three-dimensional, human tissue constructs. Margulis, A., Zhang, W., Alt-Holland, A., Crawford, H.C., Fusenig, N.E., Garlick, J.A. Cancer Res. (2005) [Pubmed]
  11. Regulation of lysophosphatidic acid-induced epidermal growth factor receptor transactivation and interleukin-8 secretion in human bronchial epithelial cells by protein kinase Cdelta, Lyn kinase, and matrix metalloproteinases. Zhao, Y., He, D., Saatian, B., Watkins, T., Spannhake, E.W., Pyne, N.J., Natarajan, V. J. Biol. Chem. (2006) [Pubmed]
  12. Matrix metalloproteinase-dependent activation of latent transforming growth factor-beta controls the conversion of osteoblasts into osteocytes by blocking osteoblast apoptosis. Karsdal, M.A., Larsen, L., Engsig, M.T., Lou, H., Ferreras, M., Lochter, A., Delaissé, J.M., Foged, N.T. J. Biol. Chem. (2002) [Pubmed]
  13. Glucagon-like peptide 1 induces pancreatic beta-cell proliferation via transactivation of the epidermal growth factor receptor. Buteau, J., Foisy, S., Joly, E., Prentki, M. Diabetes (2003) [Pubmed]
  14. Proximal events in signaling by plasma membrane estrogen receptors. Razandi, M., Pedram, A., Park, S.T., Levin, E.R. J. Biol. Chem. (2003) [Pubmed]
  15. Matrix metalloproteinase 3 is present in the cell nucleus and is involved in apoptosis. Si-Tayeb, K., Monvoisin, A., Mazzocco, C., Lepreux, S., Decossas, M., Cubel, G., Taras, D., Blanc, J.F., Robinson, D.R., Rosenbaum, J. Am. J. Pathol. (2006) [Pubmed]
  16. Transforming growth factor-beta-induced osteoblast elongation regulates osteoclastic bone resorption through a p38 mitogen-activated protein kinase- and matrix metalloproteinase-dependent pathway. Karsdal, M.A., Fjording, M.S., Foged, N.T., Delaissé, J.M., Lochter, A. J. Biol. Chem. (2001) [Pubmed]
  17. Matrix metalloproteinase inhibitors suppress transforming growth factor-beta-induced subcapsular cataract formation. Dwivedi, D.J., Pino, G., Banh, A., Nathu, Z., Howchin, D., Margetts, P., Sivak, J.G., West-Mays, J.A. Am. J. Pathol. (2006) [Pubmed]
  18. T cell gelatinases mediate basement membrane transmigration in vitro. Leppert, D., Waubant, E., Galardy, R., Bunnett, N.W., Hauser, S.L. J. Immunol. (1995) [Pubmed]
  19. Transmigration: a new property of mature multinucleated osteoclasts. Saltel, F., Chabadel, A., Zhao, Y., Lafage-Proust, M.H., Cl??zardin, P., Jurdic, P., Bonnelye, E. J. Bone Miner. Res. (2006) [Pubmed]
  20. Mutation analysis of membrane type-1 matrix metalloproteinase (MT1-MMP). The role of the cytoplasmic tail Cys(574), the active site Glu(240), and furin cleavage motifs in oligomerization, processing, and self-proteolysis of MT1-MMP expressed in breast carcinoma cells. Rozanov, D.V., Deryugina, E.I., Ratnikov, B.I., Monosov, E.Z., Marchenko, G.N., Quigley, J.P., Strongin, A.Y. J. Biol. Chem. (2001) [Pubmed]
  21. Angiotensin II activates matrix metalloproteinase type II and mimics age-associated carotid arterial remodeling in young rats. Wang, M., Zhang, J., Spinetti, G., Jiang, L.Q., Monticone, R., Zhao, D., Cheng, L., Krawczyk, M., Talan, M., Pintus, G., Lakatta, E.G. Am. J. Pathol. (2005) [Pubmed]
  22. Cytochrome P450 epoxygenases 2C8 and 2C9 are implicated in hypoxia-induced endothelial cell migration and angiogenesis. Michaelis, U.R., Fisslthaler, B., Barbosa-Sicard, E., Falck, J.R., Fleming, I., Busse, R. J. Cell. Sci. (2005) [Pubmed]
  23. Proteinases of common pathogenic bacteria degrade and inactivate the antibacterial peptide LL-37. Schmidtchen, A., Frick, I.M., Andersson, E., Tapper, H., Björck, L. Mol. Microbiol. (2002) [Pubmed]
  24. TIMP-1 inhibits microvascular endothelial cell migration by MMP-dependent and MMP-independent mechanisms. Akahane, T., Akahane, M., Shah, A., Connor, C.M., Thorgeirsson, U.P. Exp. Cell Res. (2004) [Pubmed]
  25. Up-regulation of vascular endothelial growth factor by membrane-type 1 matrix metalloproteinase stimulates human glioma xenograft growth and angiogenesis. Deryugina, E.I., Soroceanu, L., Strongin, A.Y. Cancer Res. (2002) [Pubmed]
  26. Evidence for a role of ADAM17 (TACE) in the regulation of platelet glycoprotein V. Rabie, T., Strehl, A., Ludwig, A., Nieswandt, B. J. Biol. Chem. (2005) [Pubmed]
  27. ADAM10-mediated release of complement membrane cofactor protein during apoptosis of epithelial cells. Hakulinen, J., Keski-Oja, J. J. Biol. Chem. (2006) [Pubmed]
  28. Matrix metalloproteinase activity modulates tumor size, cell motility, and cell invasiveness in murine aggressive fibromatosis. Kong, Y., Poon, R., Nadesan, P., Di Muccio, T., Fodde, R., Khokha, R., Alman, B.A. Cancer Res. (2004) [Pubmed]
  29. Matrix metalloproteinase(s) mediate(s) NO-induced dissociation of beta-catenin from membrane bound E-cadherin and formation of nuclear beta-catenin/LEF-1 complex. Mei, J.M., Borchert, G.L., Donald, S.P., Phang, J.M. Carcinogenesis (2002) [Pubmed]
  30. Administration of a matrix metalloproteinase inhibitor after hemorrhage improves cardiovascular and hepatocellular function. Wang, P., Ba, Z.F., Galardy, R.E., Chaudry, I.H. Shock (1996) [Pubmed]
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