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Chemical Compound Review

Marimastat     (2R,3S)-N-[(1S)-2,2-dimethyl- 1...

Synonyms: CHEMBL279785, CHEBI:50662, BB-2516, NSC-689451, NSC-719333, ...
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Disease relevance of BB-2516

  • Patients treated with marimastat were more likely to develop grade 2 or 3 musculoskeletal toxicity (MST), a known complication of the drug indicative of achieving a biologic effect, compared with patients administered placebo (63% v 22%, respectively; P < .0001) [1].
  • CONCLUSION: The results of this study provide evidence of a dose response for marimastat in patients with advanced pancreatic cancer [2].
  • Randomized 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 [1].
  • Marimastat was administered orally at 25, 50, or 100 mg twice daily to consecutive groups of patients with advanced lung cancer [3].
  • Prospective, randomized, double-blind, placebo-controlled trial of marimastat after response to first-line chemotherapy in patients with small-cell lung cancer: a trial of the National Cancer Institute of Canada-Clinical Trials Group and the European Organization for Research and Treatment of Cancer [4].

Psychiatry related information on BB-2516


High impact information on BB-2516

  • We demonstrated that metalloproteinases (MMPs), and most likely MMP-9, are required for intravasation by showing that marimastat, an inhibitor of MMPs, reduced intravasation by more than 90%, and that only tumor cell lines expressing MMP-9 intravasated [6].
  • CONCLUSIONS: Irrespective of the acute luminal gain by balloon dilation, the oral MMP inhibitor marimastat inhibited constrictive arterial remodeling in favor of both neutral and expansive remodeling [7].
  • EMMPRIN-expressing cells also exhibited enhanced invasive potential in vitro, and the use of amiloride (uPA inhibitor) and marimastat (MMP inhibitor) showed that the two proteolytic systems reduced alone and in combination the invasive potential mediated through EMMPRIN [8].
  • In addition to TGF-alpha release, GRP induced amphiregulin, but not EGF, secretion into HNSCC cell culture medium, an effect that was blocked by the MMP inhibitor marimastat [9].
  • PATIENTS AND METHODS: One hundred seventy-nine eligible patients were randomly assigned to receive oral marimastat (10 mg bid; n = 114) or a placebo (n = 65) within 3 to 6 weeks of completing six to eight cycles of first-line doxorubicin- and/or taxane-containing chemotherapy for metastatic disease [1].

Chemical compound and disease context of BB-2516


Biological context of BB-2516


Anatomical context of BB-2516


Associations of BB-2516 with other chemical compounds

  • Gelatinase activity of ADAM 12 was completely abrogated by zinc chelators 1,10-phenanthroline and EDTA and was partially inhibited by the hydroxamate inhibitor Marimastat [20].
  • Phase III clinical trials initiated in 1997-98 using marimastat, prinomastat (AG3340), and BAY 12-9566 alone or in combination with standard chemotherapy in patients with advanced cancers (lung, prostate, pancreas, brain, GI tract) have recently been reported; no clinical efficacy was demonstrated [21].
  • Matrix metalloproteinase inhibition as a novel anticancer strategy: a review with special focus on batimastat and marimastat [22].
  • We studied the inhibitory effect of various hydroxamate MMP inhibitors, including known inhibitors such as BB-94, BB-2516, GM6001, and Ro31-9790, on a deletion mutant of MT1-MMP lacking the transmembrane domain (DeltaMT1) to further characterize the enzyme and develop a selective inhibitor for MT1-MMP [23].
  • Current inhibitors of TACE such as succinate-based hydroxamic acids exemplified by Marimastat (TACE IC(50): 3.8 nM; blood IC(50): 7 microM) and BB1101 (TACE IC(50): 0.2 nM; blood IC(50): 2.3 microM) suffer from modest potency in blood and poor in vivo properties [24].

Gene context of BB-2516

  • The release of sGAG correlated with the concentration of MMP-1 and was inhibited by the broad-range MMP inhibitor marimastat in a dose-dependent manner [25].
  • It is shown herein that the dithiols are significantly less efficient (>100-fold) than marimastat, a broad-spectrum MMP inhibitor, in enhancing pro-MMP-2 activation in cells infected to express MT1-MMP, consistent with the lower affinity of the dithiols toward MT1-MMP [26].
  • Inhibition of TNFR1 release by the metalloprotease inhibitor BB-2516 results in a significant increase of the 42 kDa SODD protein without affecting cell survival in sensitive or resistant HT cells [27].
  • Instead of TIMP-2, various MMP inhibitors (MMPI) such as BB-2516 have been investigated with regard to suppression of tumor progression and improvement of prognosis in patients with advanced cancers, which resulted in no clinical efficacy [28].
  • Combining Wf-536 with the MMP inhibitor Marimastat greatly enhanced in vitro inhibition of endothelial vacuolation, lumen and cord formation, and VEGF- and HGF-stimulated endothelial sprout formation from aorta [29].

Analytical, diagnostic and therapeutic context of BB-2516


  1. Randomized 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. Sparano, J.A., Bernardo, P., Stephenson, P., Gradishar, W.J., Ingle, J.N., Zucker, S., Davidson, N.E. J. Clin. Oncol. (2004) [Pubmed]
  2. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. Bramhall, S.R., Rosemurgy, A., Brown, P.D., Bowry, C., Buckels, J.A. J. Clin. Oncol. (2001) [Pubmed]
  3. Phase I trial of Marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer. Wojtowicz-Praga, S., Torri, J., Johnson, M., Steen, V., Marshall, J., Ness, E., Dickson, R., Sale, M., Rasmussen, H.S., Chiodo, T.A., Hawkins, M.J. J. Clin. Oncol. (1998) [Pubmed]
  4. Prospective, randomized, double-blind, placebo-controlled trial of marimastat after response to first-line chemotherapy in patients with small-cell lung cancer: a trial of the National Cancer Institute of Canada-Clinical Trials Group and the European Organization for Research and Treatment of Cancer. Shepherd, F.A., Giaccone, G., Seymour, L., Debruyne, C., Bezjak, A., Hirsh, V., Smylie, M., Rubin, S., Martins, H., Lamont, A., Krzakowski, M., Sadura, A., Zee, B. J. Clin. Oncol. (2002) [Pubmed]
  5. Matrix metalloproteinase inhibitors: present achievements and future prospects. Denis, L.J., Verweij, J. Investigational new drugs. (1997) [Pubmed]
  6. Requirement for specific proteases in cancer cell intravasation as revealed by a novel semiquantitative PCR-based assay. Kim, J., Yu, W., Kovalski, K., Ossowski, L. Cell (1998) [Pubmed]
  7. Oral matrix metalloproteinase inhibition and arterial remodeling after balloon dilation: an intravascular ultrasound study in the pig. Sierevogel, M.J., Pasterkamp, G., Velema, E., de Jaegere, P.P., de Smet, B.J., Verheijen, J.H., de Kleijn, D.P., Borst, C. Circulation (2001) [Pubmed]
  8. Extracellular Matrix Metalloproteinase Inducer Up-regulates the Urokinase-Type Plasminogen Activator System Promoting Tumor Cell Invasion. Quemener, C., Gabison, E.E., Na??mi, B., Lescaille, G., Bougatef, F., Podgorniak, M.P., Labarch??de, G., Lebb??, C., Calvo, F., Menashi, S., Mourah, S. Cancer Res. (2007) [Pubmed]
  9. SRC family kinases mediate epidermal growth factor receptor ligand cleavage, proliferation, and invasion of head and neck cancer cells. Zhang, Q., Thomas, S.M., Xi, S., Smithgall, T.E., Siegfried, J.M., Kamens, J., Gooding, W.E., Grandis, J.R. Cancer Res. (2004) [Pubmed]
  10. Phase II trial of temozolomide plus the matrix metalloproteinase inhibitor, marimastat, in recurrent and progressive glioblastoma multiforme. Groves, M.D., Puduvalli, V.K., Hess, K.R., Jaeckle, K.A., Peterson, P., Yung, W.K., Levin, V.A. J. Clin. Oncol. (2002) [Pubmed]
  11. The effect of an inhibitor of matrix metalloproteinases on colonic inflammation in a trinitrobenzenesulphonic acid rat model of inflammatory bowel disease. Sykes, A.P., Bhogal, R., Brampton, C., Chander, C., Whelan, C., Parsons, M.E., Bird, J. Aliment. Pharmacol. Ther. (1999) [Pubmed]
  12. Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomised trial. Bramhall, S.R., Hallissey, M.T., Whiting, J., Scholefield, J., Tierney, G., Stuart, R.C., Hawkins, R.E., McCulloch, P., Maughan, T., Brown, P.D., Baillet, M., Fielding, J.W. Br. J. Cancer (2002) [Pubmed]
  13. Crystal structure of the catalytic domain of human ADAM33. Orth, P., Reichert, P., Wang, W., Prosise, W.W., Yarosh-Tomaine, T., Hammond, G., Ingram, R.N., Xiao, L., Mirza, U.A., Zou, J., Strickland, C., Taremi, S.S., Le, H.V., Madison, V. J. Mol. Biol. (2004) [Pubmed]
  14. Matrix metalloproteinase inhibition impairs the processing, formation and mineralization of dental tissues during mouse molar development. Bourd-Boittin, K., Fridman, R., Fanchon, S., Septier, D., Goldberg, M., Menashi, S. Exp. Cell Res. (2005) [Pubmed]
  15. Inhibition of metalloproteinases enhances the internalization of anti-CD30 antibody Ki-3 and the cytotoxic activity of Ki-3 immunotoxin. Hansen, H.P., Matthey, B., Barth, S., Kisseleva, T., Mokros, T., Davies, S.J., Beckett, R.P., Foelster-Holst, R., Lange, H.H., Engert, A., Lemke, H. Int. J. Cancer (2002) [Pubmed]
  16. Broad-spectrum matrix metalloproteinase inhibitor marimastat-induced musculoskeletal side effects in rats. Renkiewicz, R., Qiu, L., Lesch, C., Sun, X., Devalaraja, R., Cody, T., Kaldjian, E., Welgus, H., Baragi, V. Arthritis Rheum. (2003) [Pubmed]
  17. Evaluating antiangiogenesis agents in the clinic: the Eastern Cooperative Oncology Group Portfolio of Clinical Trials. Sparano, J.A., Gray, R., Giantonio, B., O'Dwyer, P., Comis, R.L. Clin. Cancer Res. (2004) [Pubmed]
  18. A synthetic matrix metalloproteinase inhibitor prevents squamous carcinoma cell proliferation by interfering with epidermal growth factor receptor autocrine loops. O-Charoenrat, P., Rhys-Evans, P., Eccles, S. Int. J. Cancer (2002) [Pubmed]
  19. Marimastat inhibits neointimal thickening in a model of human vein graft stenosis. Porter, K.E., Loftus, I.M., Peterson, M., Bell, P.R., London, N.J., Thompson, M.M. The British journal of surgery. (1998) [Pubmed]
  20. ADAM 12 cleaves extracellular matrix proteins and correlates with cancer status and stage. Roy, R., Wewer, U.M., Zurakowski, D., Pories, S.E., Moses, M.A. J. Biol. Chem. (2004) [Pubmed]
  21. Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Zucker, S., Cao, J., Chen, W.T. Oncogene (2000) [Pubmed]
  22. Matrix metalloproteinase inhibition as a novel anticancer strategy: a review with special focus on batimastat and marimastat. Rasmussen, H.S., McCann, P.P. Pharmacol. Ther. (1997) [Pubmed]
  23. Inhibition of membrane-type 1 matrix metalloproteinase by hydroxamate inhibitors: an examination of the subsite pocket. Yamamoto, M., Tsujishita, H., Hori, N., Ohishi, Y., Inoue, S., Ikeda, S., Okada, Y. J. Med. Chem. (1998) [Pubmed]
  24. New alpha-substituted succinate-based hydroxamic acids as TNFalpha convertase inhibitors. Barlaam, B., Bird, T.G., Lambert-Van Der Brempt, C., Campbell, D., Foster, S.J., Maciewicz, R. J. Med. Chem. (1999) [Pubmed]
  25. Functional characterization of adherent synovial fluid cells in rheumatoid arthritis: destructive potential in vitro and in vivo. Neidhart, M., Seemayer, C.A., Hummel, K.M., Michel, B.A., Gay, R.E., Gay, S. Arthritis Rheum. (2003) [Pubmed]
  26. Design, synthesis, and characterization of potent, slow-binding inhibitors that are selective for gelatinases. Bernardo, M.M., Brown, S., Li, Z.H., Fridman, R., Mobashery, S. J. Biol. Chem. (2002) [Pubmed]
  27. Altered signaling of TNFalpha-TNFR1 and SODD/BAG4 is responsible for radioresistance in human HT-R15 cells. Eichholtz-Wirth, H., Sagan, D. Anticancer Res. (2002) [Pubmed]
  28. Recent advances in the regulation of matrix metalloproteinase 2 activation: from basic research to clinical implication (Review). Yoshizaki, T., Sato, H., Furukawa, M. Oncol. Rep. (2002) [Pubmed]
  29. Rho kinase and matrix metalloproteinase inhibitors cooperate to inhibit angiogenesis and growth of human prostate cancer xenotransplants. Somlyo, A.V., Phelps, C., Dipierro, C., Eto, M., Read, P., Barrett, M., Gibson, J.J., Burnitz, M.C., Myers, C., Somlyo, A.P. FASEB J. (2003) [Pubmed]
  30. Development of matrix metalloproteinase inhibitors in cancer therapy. Hidalgo, M., Eckhardt, S.G. J. Natl. Cancer Inst. (2001) [Pubmed]
  31. Inhibition of tumour growth by marimastat in a human xenograft model of gastric cancer: relationship with levels of circulating CEA. Watson, S.A., Morris, T.M., Collins, H.M., Bawden, L.J., Hawkins, K., Bone, E.A. Br. J. Cancer (1999) [Pubmed]
  32. Phase II study of high central dose Gamma Knife radiosurgery and marimastat in patients with recurrent malignant glioma. Larson, D.A., Prados, M., Lamborn, K.R., Smith, V., Sneed, P.K., Chang, S., Nicholas, K.M., Wara, W.M., Devriendt, D., Kunwar, S., Berger, M., McDermott, M.W. Int. J. Radiat. Oncol. Biol. Phys. (2002) [Pubmed]
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