Cancer and Metastasis Reviews

, Volume 25, Issue 1, pp 115–136 | Cite as

Recent advances in MMP inhibitor design

  • Jed F. Fisher
  • Shahriar MobasheryEmail author


The search for an MMP inhibitor with anticancer efficacy is a nearly three-decade endeavor. This inhibitor is yet to be found. The reasons for this failure include shortcomings in the chemistry of these compounds (including broad MMP sub-type selectivity, metabolic lability, and toxicity) as well as the emerging, and arguably extraordinary, complexity of MMP cell (and cancer) biology. Together these suggest that the successful anticancer inhibitor must possess MMP selectivity against the MMP subtype whose involvement is critical, yet highly temporally (with respect to metastatic progression) and mechanistically (with respect to matrix degradation) regulated. This review summarizes the progression of chemical structure and mechanistic thinking toward these objectives, with emphasis on the disappointment, the perseverance, and the resilient optimism that such an inhibitor is there to be discovered.


Matrix metalloprotease Metalloproteinase gelatinase Collagenase 


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  1. 1.
    Breuer E, Frant J, Reich R: Recent non-hydroxamate matrix metalloproteinase inhibitors. Expert Opin Ther Patents 15: 253–269, 2005Google Scholar
  2. 2.
    Hodgson J: Remodelling MMPIs. Biotechnology 13: 554–557, 1995PubMedGoogle Scholar
  3. 3.
    Ramnath N, Creaven PJ: Matrix metalloproteinase inhibitors. Curr Oncol Rep 6: 96–102, 2004PubMedGoogle Scholar
  4. 4.
    Handsley MM, Edwards DR: Metalloproteinases and their inhibitors in tumor angiogenesis. Int J Cancer 115: 849–860, 2005PubMedGoogle Scholar
  5. 5.
    Wallach J, Hornebeck W: Matrix metalloproteases and cancer. Novel perspectives in the role and control of matrix metalloproteinases in tumor progression. Biochimie 87: 241, 2005Google Scholar
  6. 6.
    Bjorklund M, Koivunen E: Gelatinase-mediated migration and invasion of cancer cells. Biochim Biophys Acta (Rev. Cancer) 1755: 37–69, 2005Google Scholar
  7. 7.
    Demers M, Couillard J, Belanger S, St-Pierre Y: New roles for matrix metalloproteinases in metastasis. Crit Rev Immunol 25: 493–523, 2005PubMedGoogle Scholar
  8. 8.
    Fingleton B: Matrix metalloproteinases: Roles in cancer and metastasis. Front Biosci 11: 479–491, 2006PubMedGoogle Scholar
  9. 9.
    Matter H, Schudok M: Recent advances in the design of matrix metalloprotease inhibitors. Curr Opin Drug Discov Devel 7: 513–535, 2004PubMedGoogle Scholar
  10. 10.
    Cuniasse P, Devel L, Makaritis A, Beau F, Georgiadis D, Matziari M, Yiotakis A, Dive V: Future challenges facing the development of specific active-site-directed synthetic inhibitors of MMPs. Biochimie 87: 393–402, 2005PubMedGoogle Scholar
  11. 11.
    Jani M, Tordai H, Trexler M, Banyai L, Patthy L: Hydroxamate-based peptide inhibitors of matrix metalloprotease 2. Biochimie 87: 385–392, 2005PubMedGoogle Scholar
  12. 12.
    Kontogiorgis CA, Papaioannou P, Hadjipavlou-Litina DJ: Matrix metalloproteinase inhibitors: A review on pharmacophore mapping and (Q)SARs results. Curr Med Chem 12: 339–355, 2005PubMedGoogle Scholar
  13. 13.
    Mannello F, Tonti G, Papa S: Matrix metalloproteinase inhibitors as anticancer therapeutics. Curr Cancer Drug Targets 5: 285–298, 2005PubMedGoogle Scholar
  14. 14.
    Maskos K: Crystal structures of MMPs in complex with physiological and pharmacological inhibitors. Biochimie 87: 249–263, 2005PubMedGoogle Scholar
  15. 15.
    Rao BG: Recent developments in the design of specific Matrix Metalloproteinase inhibitors aided by structural and computational studies. Curr Pharm Des 11: 295–322, 2005PubMedGoogle Scholar
  16. 16.
    Tyndall JD, Nall T, Fairlie DP: Proteases universally recognize beta strands in their active sites. Chem Rev 105: 973–999, 2005PubMedGoogle Scholar
  17. 17.
    Vihinen P, Ala-aho R, Kahari VM: Matrix metalloproteinases as therapeutic targets in cancer. Curr Cancer Drug Targets 5: 203–220, 2005PubMedGoogle Scholar
  18. 18.
    Wasserman ZR: Making a new turn in matrix metalloprotease inhibition. Chem Biol 12: 143–144, 2005PubMedGoogle Scholar
  19. 19.
    Pender SL, MacDonald TT: Matrix metalloproteinases and the gut—new roles for old enzymes. Curr Opin Pharmacol 4: 546–550, 2004PubMedGoogle Scholar
  20. 20.
    Parks WC, Wilson CL, Lopez-Boado YS: Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol 4: 617–629, 2004PubMedGoogle Scholar
  21. 21.
    Jian Liu K, Rosenberg GA: Matrix metalloproteinases and free radicals in cerebral ischemia. Free Rad Biol Med 39: 71–80, 2005PubMedGoogle Scholar
  22. 22.
    Yong VW: Metalloproteinases: Mediators of Pathology and Regeneration in the CNS. Nat Rev Neurosci 6: 931–944, 2005PubMedGoogle Scholar
  23. 23.
    Ferrara N, Kerbel RS: Angiogenesis as a therapeutic target. Nature 438: 967–974, 2005PubMedGoogle Scholar
  24. 24.
    Tayebjee MH, Lip GY, MacFadyen RJ: Matrix metalloproteinases in coronary artery disease: clinical and therapeutic implications and pathological significance. Curr Med Chem 12: 917–925, 2005PubMedGoogle Scholar
  25. 25.
    Demedts IK, Brusselle GG, Bracke KR, Vermaelen KY, Pauwels RA: Matrix metalloproteinases in asthma and COPD. Curr Opin Pharmacol 5: 257–263, 2005PubMedGoogle Scholar
  26. 26.
    Naito Y, Yoshikawa T: Role of matrix metalloproteinases in inflammatory bowel disease. Mol Aspects Med 26: 379–390, 2005PubMedGoogle Scholar
  27. 27.
    Weigelt B, Peterse JL, van Veer LJ: Breast cancer metastasis: markers and models. Nat Rev Cancer 5: 591–602, 2005PubMedGoogle Scholar
  28. 28.
    Wieland HA, Michaelis M, Kirschbaum BJ, Rudolphi KA: Osteoarthritis—an untreatable disease? Nat Rev Drug Discov 4: 331–344, 2005PubMedGoogle Scholar
  29. 29.
    McIntyre JO, Fingleton B, Wells KS, Piston DW, Lynch CC, Gautam S, Matrisian LM: Development of a novel fluorogenic proteolytic beacon for in vivo detection and imaging of tumour-associated matrix metalloproteinase-7 activity. Biochem J 377: 617–628, 2004PubMedGoogle Scholar
  30. 30.
    Fingleton B, Menon R, Carter KJ, Overstreet PD, Hachey DL, Matrisian LM, McIntyre JO: Proteinase activity in human and murine saliva as a biomarker for proteinase inhibitor efficacy. Clin Cancer Res 10: 7865–7874, 2004PubMedGoogle Scholar
  31. 31.
    Gerlach RF, Tanus-Santos JE, Vihinen P: Circulating matrix metalloproteinase-9 levels as a biomarker of disease. Clin Cancer Res 11: 8887–8888, 2005PubMedGoogle Scholar
  32. 32.
    Kelloff GJ, Krohn KA, Larson SM, Weissleder R, Mankoff DA, Hoffman JM, Link JM, Guyton KZ, Eckelman WC, Scher HI, O'Shaughnessy J, Cheson BD, Sigman CC, Tatum JL, Mills GQ, Sullivan DC, Woodcock J: The progress and promise of molecular imaging probes in oncologic drug development. Clin Cancer Res 11: 7967–7985, 2005PubMedGoogle Scholar
  33. 33.
    Rosenberg GA: Matrix metalloproteinases biomarkers in multiple sclerosis. Lancet 365: 1291–1293, 2005PubMedGoogle Scholar
  34. 34.
    Sledge GWJ: Transforming technologies and breast cancer. Clin Breast Cancer 6: 283, 2005PubMedCrossRefGoogle Scholar
  35. 35.
    Somiari SB, Shriver CD, Heckman C, Olsen C, Hu H, Jordan R, Arciero C, Russell S, Garguilo G, Hooke J, Somiari RI: Plasma concentration and activity of matrix metalloproteinase 2 and 9 in patients with breast disease, breast cancer and at risk of developing breast cancer. Cancer Lett. 233: 98–107, 2006PubMedGoogle Scholar
  36. 36.
    Rothenberg ML, Carbone DP, Johnson DH: Improving the evaluation of new cancer treatments: challenges and opportunities. Nat Rev Cancer 3: 303–309, 2003PubMedGoogle Scholar
  37. 37.
    Millar AW, Lynch KP: Rethinking clinical trials for cytostatic drugs. Nat Rev Cancer 3: 540–545, 2003PubMedGoogle Scholar
  38. 38.
    Parulekar WR, Eisenhauer EA: Phase I trial design for solid tumor studies of targeted, non-cytotoxic agents: Theory and practice. J Natl Cancer Inst 96: 990–997, 2004PubMedGoogle Scholar
  39. 39.
    Sparano JA, Bernardo P, Stephenson P, Gradishar WJ, Ingle JN, Zucker S, Davidson NE: 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. J Clin Oncol 22: 4683–4690, 2004PubMedGoogle Scholar
  40. 40.
    Goffin JR, Anderson IC, Supko JG, Eder JPJ, Shapiro GI, Lynch TJ, Shipp M, Johnson BE, Skarin AT: Phase I trial of the matrix metalloproteinase inhibitor marimastat combined with carboplatin and paclitaxel in patients with advanced non-small cell lung cancer. Clin Cancer Res 11: 3417–3424, 2005PubMedGoogle Scholar
  41. 41.
    Jones PH, Christodoulos K, Dobbs N, Thavasu P, Balkwill F, Blann AD, Caine GJ, Kumar S, Kakkar AJ, Gompertz N, Talbot DC, Ganesan TS, Harris AL: Combination antiangiogenesis therapy with marimastat, captopril and fragmin in patients with advanced cancer. Br J Cancer 91: 30–36, 2004PubMedGoogle Scholar
  42. 42.
    Rosenbaum E, Zahurak M, Sinibaldi V, Carducci MA, Pili R, Laufer M, DeWeese TL, Eisenberger MA: Marimastat in the treatment of patients with biochemically relapsed prostate cancer: A prospective randomized, double-blind, phase I/II trial. Clin Cancer Res 11: 4437–4443, 2005PubMedGoogle Scholar
  43. 43.
    Reiter LA, Robinson RP, McClure KF, Jones CS, Reese MR, Mitchell PG, Otterness IG, Bliven ML, Liras J, Cortina SR, Donahue KM, Eskra JD, Griffiths RJ, Lame ME, Lopez-Anaya A, Martinelli GJ, McGahee SM, Yocum SA, Lopresti-Morrow LL, Tobiassen LM, Vaughn-Bowser ML: Pyran-containing sulfonamide hydroxamic acids: Potent MMP inhibitors that spare MMP-1. Bioorg Med Chem Lett 14: 3389–3395, 2004PubMedGoogle Scholar
  44. 44.
    Zask A, Kaplan J, Du X, MacEwan G, Sandanayaka V, Eudy N, Levin J, Jin G, Xu J, Cummons T, Barone D, Ayral-Kaloustian S, Skotnicki J: Synthesis and SAR of diazepine and thiazepine TACE and MMP inhibitors. Bioorg Med Chem Lett 15: 1641–1645, 2005PubMedGoogle Scholar
  45. 45.
    Duan JJ, Lu Z, Wasserman ZR, Liu R, Covington MB, Decicco CP: Non-hydroxamate 5-phenylpyrimidine-2,4,6-trione derivatives as selective inhibitors of tumor necrosis factor-alpha converting enzyme. Bioorg Med Chem Lett 15: 2970–2973, 2005PubMedGoogle Scholar
  46. 46.
    Andreini C, Banci L, Bertini I, Rosato A: Counting the Zinc-Proteins Encoded in the Human Genome. J Proteome Res 5: 196–201, 2006PubMedGoogle Scholar
  47. 47.
    Wall L, Talbot DC, Bradbury P, Jodrell DI: A phase I and pharmacological study of the matrix metalloproteinase inhibitor BB–3644 in patients with solid tumours. Br J Cancer 90: 800–804, 2004PubMedGoogle Scholar
  48. 48.
    Jozic D, Bourenkov G, Lim NH, Visse R, Nagase H, Bode W, Maskos K: X-ray structure of human proMMP-1: New insights into procollagenase activation and collagen binding. J Biol Chem 280: 9578–9585, 2005PubMedGoogle Scholar
  49. 49.
    Tsai KC, Lin TH: A ligand-based molecular modeling study on some matrix metalloproteinase-1 inhibitors using several 3D QSAR techniques. J Chem Inf Comput Sci 44: 1857–1871, 2004PubMedGoogle Scholar
  50. 50.
    Irwin JJ, Raushel FM, Shoichet BK: Virtual screening against metalloenzymes for inhibitors and substrates. Biochemistry 44: 12316–12328, 2005PubMedGoogle Scholar
  51. 51.
    Bertini I, Fragai M, Giachetti A, Luchinat C, Maletta M, Parigi G, Yeo KJ: Combining in silico tools and NMR data to validate protein-ligand structural models: Application to matrix metalloproteinases. J Med Chem 48: 7544–7559, 2005PubMedGoogle Scholar
  52. 52.
    Matter H, Schudok M, Elshorst B, Jacobs DM, Saxena K, Kogler H: QSAR-by-NMR: Quantitative insights into structural determinants for binding affinity by analysis of 1H/15N chemical shift differences in MMP-3 ligands. Bioorg Med Chem Lett 15: 1779–1783, 2005PubMedGoogle Scholar
  53. 53.
    Lukacova V, Zhang Y, Mackov M, Baricic P, Raha S, Calvo JA, Balaz S: Similarity of binding sites of human matrix metalloproteinases. J Biol Chem 279: 14194–14200, 2004PubMedGoogle Scholar
  54. 54.
    Takahashi K, Ikura M, Habashita H, Nishizaki M, Sugiura T, Yamamoto S, Nakatani S, Ogawa K, Ohno H, Nakai H, Toda M: Novel matrix metalloproteinase inhibitors: Generation of lead compounds by the in silico fragment-based approach. Bioorg Med Chem 13: 4527–4543, 2005PubMedGoogle Scholar
  55. 55.
    Khandelwal A, Lukacova V, Comez D, Kroll DM, Raha S, Balaz S: A combination of docking, QM/MM methods, and MD simulation for binding affinity estimation of metalloprotein ligands. J Med Chem 48: 5437–5447, 2005PubMedGoogle Scholar
  56. 56.
    Lukacova V, Zhang Y, Kroll DM, Raha S, Comez D, Balaz S: A comparison of the binding sites of matrix metalloproteinases and tumor necrosis factor-alpha converting enzyme: Implications for selectivity. J Med Chem 48: 2361–2370, 2005PubMedGoogle Scholar
  57. 57.
    Pirard B, Matter H: Matrix Metalloproteinase Target Family Landscape: A Chemometrical Approach to Ligand Selectivity Based on Protein Binding Site Analysis. J Med Chem 49: 51–69, 2006PubMedGoogle Scholar
  58. 58.
    Wasserman ZR, Duan JJ, Voss ME, Xue CB, Cherney RJ, Nelson DJ, Hardman KD, Decicco CP: Identification of a selectivity determinant for inhibition of tumor necrosis factor-alpha converting enzyme by comparative modeling. Chem Biol 10: 215–223, 2003PubMedGoogle Scholar
  59. 59.
    Xu X, Chen Z, Wang Y, Yamada Y, Steffensen B: Functional basis for the overlap in ligand interactions and substrate specificities of matrix metalloproteinases-9 and -2. Biochem J 392: 127–134, 2005PubMedGoogle Scholar
  60. 60.
    Toth M, Osenkowski P, Hesek D, Brown S, Meroueh S, Sakr W, Mobashery S, Fridman R: Cleavage at the stem region releases an active ectodomain of the membrane type 1 matrix metalloproteinase. Biochem J 387: 497–506, 2005PubMedGoogle Scholar
  61. 61.
    Pelman GR, Morrison CJ, Overall CM: Pivotal molecular determinants of peptidic and collagen triple helicase activities reside in the S3' subsite of matrix metalloproteinase 8 (MMP-8): the role of hydrogen bonding potential of ASN188 and TYR189 and the connecting cis bond. J Biol Chem 280: 2370–2377, 2005PubMedGoogle Scholar
  62. 62.
    Eatock M, Cassidy J, Johnson J, Morrison R, Devlin M, Blackey R, Owen S, Choi L, Twelves C: A dose-finding and pharmacokinetic study of the matrix metalloproteinase inhibitor MMI270 (previously termed CGS27023A) with 5-FU and folinic acid. Cancer Chemother Pharmacol 55: 39–46, 2005PubMedGoogle Scholar
  63. 63.
    Borkakoti N: Matrix metalloprotease inhibitors: Design from structure. Biochem Soc Trans 32: 17–20, 2004PubMedGoogle Scholar
  64. 64.
    Fujino H, Kondo K, Ishikura H, Maki H, Kinoshita H, Miyoshi T, Takahashi Y, Sawada N, Takizawa H, Nagao T, Sakiyama S, Monden Y: Matrix metalloproteinase inhibitor MMI-166 inhibits lymphogenous metastasis in an orthotopically implanted model of lung cancer. Clin Cancer Res 6: 3944–3948, 2000Google Scholar
  65. 65.
    Hojo K, Maki H, Sawada TY, Maekawa R, Yoshioka T: Augmented growth inhibition of B16-BL6 melanoma by combined treatment with a selective matrix metalloproteinase inhibitor, MMI-166, and cytotoxic agents. Anticancer Res 22: 3253–3259, 2002PubMedGoogle Scholar
  66. 66.
    Ikonomidis JS, Hendrick JW, Parkhurst AM, Herron AR, Escobar PG, Dowdy KB, Stroud RE, Hapke E, Zile M, Spinale FG: Accelerated LV remodeling after myocardial infarction in TIMP-1-deficient mice: Effects of exogenous MMP inhibition. Am J Physiol Heart Circ Physiol 288: H149–158, 2005PubMedGoogle Scholar
  67. 67.
    Kassiri Z, Oudit GY, Sanchez O, Dawood F, Mohammed FF, Nuttall RK, Edwards DR, Liu PP, Backx PH, Khokha R: Combination of tumor necrosis factor-alpha ablation and matrix metalloproteinase inhibition prevents heart failure after pressure overload in tissue inhibitor of metalloproteinase-3 knock-out mice. Circ Res 97: 380–390, 2005PubMedGoogle Scholar
  68. 68.
    Wada CK, Holms JH, Curtin ML, Dai Y, Florjancic AS, Garland RB, Guo Y, Heyman HR, Stacey JR, Steinman DH, Albert DH, Bouska JJ, Elmore IN, Goodfellow CL, Marcotte PA, Tapang P, Morgan DW, Michaelides MR, Davidsen SK: Phenoxyphenyl sulfone N-formylhydroxylamines (retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors. J Med Chem 45: 219–232, 2002PubMedGoogle Scholar
  69. 69.
    Wada CK: The evolution of the matrix metalloproteinase inhibitor drug discovery program at Abbott laboratories. Curr Top Med Chem 4: 1255–1267, 2004PubMedGoogle Scholar
  70. 70.
    Scatena R: Prinomastat, a hydroxamate-based matrix metalloproteinase inhibitor. A novel pharmacological approach for tissue remodelling-related diseases. Expert Opin Investig Drugs 9: 2159–2165, 2000PubMedGoogle Scholar
  71. 71.
    Arlt M, Kopitz C, Pennington C, Watson KLM, Krell HW, Bode W, Gansbacher B, Khokha R, Edwards DR, Kruger A: Increase in Gelatinase-specificity of Matrix Metalloproteinase Inhibitors Correlates with Antimetastatic Efficacy in a T-Cell Lymphoma Model. Clin Cancer Res 7: 1912–1922, 2001Google Scholar
  72. 72.
    Deryugina EI, Ratnikov BI, Strongin AY: Prinomastat, a hydroxamate inhibitor of matrix metalloproteinases, has a complex effect on migration of breast carcinoma cells. Int J Cancer 104: 533–541, 2003PubMedGoogle Scholar
  73. 73.
    Kruger A, Soeltl R, Sopov I, Kopitz C, Arlt M, Magdolen V, Harbeck N, Gansbacher B, Schmitt M: Hydroxamate—Type Matrix Metalloproteinase Inhibitor Batimastat Promotes Liver Metastasis. Cancer Res 62: 5543–5550, 2002PubMedGoogle Scholar
  74. 74.
    Savinov AY, Rozanov DV, Golubkov VS, Wong FS, Strongin AY: Inhibition of membrane type-1 matrix metalloproteinase by cancer drugs interferes with the homing of diabetogenic T cells into the pancreas. J Biol Chem 280: 27755–27758, 2005PubMedGoogle Scholar
  75. 75.
    Ferrario A, Chantrain CF, von Tiehl K, Buckley S, Rucker N, Shalinsky DR, Shimada H, DeClerck YA, Gomer CJ: The matrix metalloproteinase inhibitor prinomastat enhances photodynamic therapy responsiveness in a mouse tumor model. Cancer Res 64: 2328–2332, 2004PubMedGoogle Scholar
  76. 76.
    Hande KR, Collier M, Paradiso L, Stuart-Smith J, Dixon M, Clendeninn N, Yeun G, Alberti D, Binger K, Wilding G: Phase I and Pharmacokinetic Study of Prinomastat, a Matrix Metalloprotease Inhibitor. Clin Cancer Res. 10: 909–915, 2004PubMedGoogle Scholar
  77. 77.
    Bissett D, O'Byrne KJ, von Pawel J, Gatzemeier U, Price A, Nicolson M, Mercier R, Mazabel E, Penning C, Zhang MH, Collier MA, Shepherd FA: Phase III study of matrix metalloproteinase inhibitor prinomastat in non-small-cell lung cancer. J Clin Oncol 23: 842–849, 2005PubMedGoogle Scholar
  78. 78.
    Lovejoy B, Welch AR, Carr S, Luong C, Broka C, Hendricks RT, Campbell JA, Walker KA, Martin R, Van Wart H, Browner MF: Crystal structures of MMP-1 and -13 reveal the structural basis for selectivity of collagenase inhibitors. Nat Struct Biol 6: 217–221, 1999PubMedGoogle Scholar
  79. 79.
    Renkiewicz R, Qiu L, Lesch C, Sun X, Devalaraja R, Cody T, Kaldjian E, Welgus H, Baragi V: Broad-spectrum matrix metalloproteinase inhibitor marimastat-induced musculoskeletal side effects in rats. Arthritis Rheum 48: 1742–1749, 2003PubMedGoogle Scholar
  80. 80.
    Aranapakam V, Grosu GT, Davis JM, Hu B, Ellingboe J, Baker JL, Skotnicki JS, Zask A, DiJoseph JF, Sung A, Sharr MA, Killar LM, Walter T, Jin G, Cowling R: Synthesis and structure-activity relationship of alpha-sulfonylhydroxamic acids as novel, orally active matrix metalloproteinase inhibitors for the treatment of osteoarthritis. J Med Chem 46: 2361–2375, 2003PubMedGoogle Scholar
  81. 81.
    Aranapakam V, Davis JM, Grosu GT, Baker J, Ellingboe J, Zask A, Levin J, Sandanayaka VP, Du M, Skotnicki JS, DiJoseph JF, Sung A, Sharr MA, Killar LM, Walter T, Jin G, Cowling R, Tillett J, Zhao W, McDevitt J, Xu ZB: Synthesis and structure-activity relationship of N-substituted 4-arylsulfonylpiperidine-4-hydroxamic acids as novel, orally active matrix metalloproteinase inhibitors for the treatment of osteoarthritis. J Med Chem 46: 2376–2396, 2003PubMedGoogle Scholar
  82. 82.
    Becker DP, Villamil CI, Barta TE, Bedell LJ, Boehm TL, Decrescenzo GA, Freskos JN, Getman DP, Hockerman S, Heintz R, Howard SC, Li M, McDonald JJ, Carron C, Funckes-Shippy CL, Mehta PP, Munie GE, Swearingen CA: Synthesis and structure-activity relationships of beta- and alpha-piperidine sulfone hydroxamic acid matrix metalloproteinase inhibitors with oral antitumor efficacy. J Med Chem 48: 6713–6730, 2005PubMedGoogle Scholar
  83. 83.
    Sani M, Candiani G, Pecker F, Malpezzi L, Zanda M: Novel highly potent, structurally simple [gamma]-trifluoromethyl [gamma]-sulfone hydroxamate inhibitor of stromelysin-1 (MMP-3). Tetrahedron Lett 46: 2393–2396, 2005Google Scholar
  84. 84.
    Rossello A, Nuti E, Carelli P, Orlandini E, Macchia M, Nencetti S, Zandomeneghi M, Balzano F, Uccello Barretta G, Albini A, Benelli R, Cercignani G, Murphy G, Balsamo A: N-i-Propoxy-N-biphenylsulfonylaminobutylhydroxamic acids as potent and selective inhibitors of MMP-2 and MT1-MMP. Bioorg Med Chem Lett 15: 1321–1326, 2005PubMedGoogle Scholar
  85. 85.
    Ishikawa T, Nishigaki F, Miyata S, Hirayama Y, Minoura K, Imanishi J, Neya M, Mizutani T, Imamura Y, Naritomi Y, Murai H, Ohkubo Y, Kagayama A, Mutoh S: Prevention of progressive joint destruction in collagen-induced arthritis in rats by a novel matrix metalloproteinase inhibitor, FR255031. Br J Pharmacol 144: 133–143, 2005PubMedGoogle Scholar
  86. 86.
    Muraishi Y, Mitani N, Fuse H, Saiki I: Effect of a matrix metalloproteinase inhibitor (ONO-4817) on lung metastasis of murine renal cell carcinoma. Anticancer Res 21: 3845–3852, 2001PubMedGoogle Scholar
  87. 87.
    Shiraga M, Yano S, Yamamoto A, Ogawa H, Goto H, Miki T, Miki K, Zhang H, Sone S: Organ heterogeneity of host-derived matrix metalloproteinase expression and its involvement in multiple-organ metastasis by lung cancer cell lines. Cancer Res 62: 5967–5973, 2002PubMedGoogle Scholar
  88. 88.
    Mori T, Nakahashi K, Kyokuwa M, Yamasaki S, Nagasawa H: A matrix metalloproteinase inhibitor, ONO-4817, retards the development of mammary tumor and the progression of uterine adenomyosis in mice. Anticancer Res 22: 3985–3988, 2002PubMedGoogle Scholar
  89. 89.
    Yamamoto A, Yano S, Shiraga M, Ogawa H, Goto H, Miki T, Zhang H, Sone S: A third-generation matrix metalloproteinase (MMP) inhibitor (ONO-4817) combined with docetaxel suppresses progression of lung micrometastasis of MMP-expressing tumor cells in nude mice. Int J Cancer 103: 822–828, 2003PubMedGoogle Scholar
  90. 90.
    Yamashita T, Fujii M, Tomita T, Ishiguro R, Tashiro M, Tokumaru Y, Imanishi Y, Kanke M, Ogawa K, Kameyama K, Otani Y: The inhibitory effect of matrix metalloproteinase inhibitor ONO-4817 on lymph node metastasis in tongue carcinoma. Anticancer Res 23: 2297–2302, 2003PubMedGoogle Scholar
  91. 91.
    Yamada A, Uegaki A, Nakamura T, Ogawa K: ONO-4817, an orally active matrix metalloproteinase inhibitor, prevents lipopolysaccharide-induced proteoglycan release from the joint cartilage in guinea pigs. Inflamm Res 49: 144–146, 2000PubMedGoogle Scholar
  92. 92.
    Masuda T, Nakayama Y: Development of a water-soluble matrix metalloproteinase inhibitor as an intra-arterial infusion drug for prevention of restenosis after angioplasty. J Med Chem 46: 3497–3501, 2003PubMedGoogle Scholar
  93. 93.
    Yoshioka M, Yokoyama N, Masuda K, Honna T, Hinode D, Nakamura R, Rouabhia M, Mayrand D, Grenier D: Effect of hydroxamic acid-based matrix metalloproteinase inhibitors on human gingival cells and Porphyromonas gingivalis. J Periodontol 74: 1219–1224, 2003PubMedGoogle Scholar
  94. 94.
    Matsuno H, Ishisaki A, Nakajima K, Kozawa O: Effect of a synthetic matrix metalloproteinase inhibitor (ONO-4817) on neointima formation in hypercholesterolemic hamsters. J Cardiovasc Pharmacol 44: 57–65, 2004PubMedGoogle Scholar
  95. 95.
    Naito Y, Takagi T, Kuroda M, Katada K, Ichikawa H, Kokura S, Yoshida N, Okanoue T, Yoshikawa T: An orally active matrix metalloproteinase inhibitor, ONO-4817, reduces dextran sulfate sodium-induced colitis in mice. Inflamm Res 53: 462–468, 2004PubMedGoogle Scholar
  96. 96.
    Levin JI, Chen JM, Laakso LM, Du M, Du X, Venkatesan AM, Sandanayaka V, Zask A, Xu J, Xu W, Zhang Y, Skotnicki JS: Acetylenic TACE inhibitors. Part 2: SAR of six-membered cyclic sulfonamide hydroxamates. Bioorg Med Chem Lett 15: 4345–4349, 2005PubMedGoogle Scholar
  97. 97.
    Zhang Y, Xu J, Levin J, Hegen M, Li G, Robertshaw H, Brennan F, Cummons T, Clarke D, Vansell N, Nickerson-Nutter C, Barone D, Mohler K, Black R, Skotnicki J, Gibbons J, Feldmann M, Frost P, Larsen G, Lin LL: Identification and characterization of 4-[[4-(2-butynyloxy)phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-(3S)thiomorpho linecarboxamide (TMI-1), a novel dual tumor necrosis factor-alpha-converting enzyme/matrix metalloprotease inhibitor for the treatment of rheumatoid arthritis. J Pharmacol Exp Ther 309: 348–355, 2004PubMedGoogle Scholar
  98. 98.
    Zhang Y, Hegen M, Xu J, Keith JC, Jin G, Du X, Cummons T, Sheppard BJ, Sun L, Zhu Y, Rao V, Wang Q, Xu W, Cowling R, Nickerson-Nutter CL, Gibbons J, Skotnicki J, Lin LL, Levin J: Characterization of (2R, 3S)-2-([[4-(2-butynyloxy)phenyl]sulfonyl]amino)-N,3-dihydroxybutanamide, a potent and selective inhibitor of TNF-alpha converting enzyme. Int Immunopharmacol 4: 1845–1857, 2004PubMedGoogle Scholar
  99. 99.
    Cherney RJ, Mo R, Meyer DT, Hardman KD, Liu R, Covington MB, Qian M, Wasserman ZR, Christ DD, Trzaskos JM, Newton RC, Decicco CP: Sultam hydroxamates as novel matrix metalloproteinase inhibitors. J Med Chem 47: 2981–2983, 2004PubMedGoogle Scholar
  100. 100.
    Cherney RJ, King BW, Gilmore JL, Liu R, Covington MB, Duan JJ, Decicco CP: Conversion of potent MMP inhibitors into selective TACE inhibitors. Bioorg Med Chem Lett 16: 1028–1031, 2006PubMedGoogle Scholar
  101. 101.
    Kocer SS, Walker SG, Zerler B, Golub LM, Simon SR: Metalloproteinase inhibitors, nonantimicrobial chemically modified tetracyclines, and ilomastat block Bacillus anthracis lethal factor activity in viable cells. Infect Immun 73: 7548–7557, 2005PubMedGoogle Scholar
  102. 102.
    Shoop W, Xiong Y, Wiltsie J, Woods A, Guo J, Pivnichny J, Felcetto T, Michael B, Bansal A, Cummings R, Cunningham B, Friedlander A, Douglas C, Patel S, Wisniewski D, Scapin G, Salowe S, Zaller D, Chapman K, Scolnick E, Schmatz D, Bartizal K, MacCoss M, Hermes J: Anthrax lethal factor inhibition. Proc Natl Acad Sci U S A 102: 7958–7963, 2005PubMedGoogle Scholar
  103. 103.
    Johnson SL, Jung D, Forino M, Chen Y, Satterthwait A, Rozanov DV, Strongin AY, Pellecchia M: Anthrax Lethal Factor Protease Inhibitors: Synthesis, SAR, and Structure–Based 3D QSAR Studies. J Med Chem 49: 27–30, 2006PubMedGoogle Scholar
  104. 104.
    Xiong Y, Wiltsie J, Woods A, Guo J, Pivnichny J, Tang W, Bansal A, Cummings R, Cunningham B, Friedlander A, Douglas C, Salowe S, Zaller D, Scolnick E, Schmatz D, Bartizal K, Hermes J, Maccoss M, Chapman K: The discovery of a potent and selective lethal factor inhibitor for adjunct therapy of anthrax infection. Bioorg Med Chem Lett 16: 964–968, 2006PubMedGoogle Scholar
  105. 105.
    Hu Y, Xiang JS, DiGrandi MJ, Du X, Ipek M, Laakso LM, Li J, Li W, Rush TS, Schmid J, Skotnicki JS, Tam S, Thomason JR, Wang Q, Levin JI: Potent, selective, and orally bioavailable matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis. Bioorg Med Chem 13: 6629–6644, 2005PubMedGoogle Scholar
  106. 106.
    Xiang JS, Hu Y, Rush TS, Thomason JR, Ipek M, Sum PE, Abrous L, Sabatini JJ, Georgiadis K, Reifenberg E, Majumdar M, Morris EA, Tam S: Synthesis and biological evaluation of biphenylsulfonamide carboxylate aggrecanase-1 inhibitors. Bioorg Med Chem Lett 16: 311–316, 2006PubMedGoogle Scholar
  107. 107.
    Ma D, Jiang Y, Chen F, Gong L, Ding K, Xu Y, Wang R, Ge A, Ren J, Li J, Li J, Ye Q: Selective inhibition of MMP isozymes and In vivo Protection against Emphysema by Substituted gamma-Keto Carboxylate. J Med Chem 49: 456–458, 2006PubMedGoogle Scholar
  108. 108.
    Naglich JG, Jure-Kunkel M, Gupta E, Fargnoli J, Henderson AJ, Lewin AC, Talbott R, Baxter A, Bird J, Savopoulos R, Wills R, Kramer RA, Trail PA: Inhibition of angiogenesis and metastasis in two murine models by the matrix metalloproteinase inhibitor, BMS-275291. Cancer Res 61: 8480–8485, 2001PubMedGoogle Scholar
  109. 109.
    Borg TK: It's the matrix! ECM, proteases, and cancer. Am J Pathol 164: 1141–1142, 2004PubMedGoogle Scholar
  110. 110.
    Maquart FX, Pasco S, Ramont L, Hornebeck W, Monboisse JC: An introduction to matrikines: Extracellular matrix-derived peptides which regulate cell activity. Implication in tumor invasion. Crit Rev Oncol Hematol 49: 199–202, 2004PubMedGoogle Scholar
  111. 111.
    Radisky DC, Bissell MJ: Cancer. Respect thy neighbor! Science 303: 775–777, 2004PubMedGoogle Scholar
  112. 112.
    Yamaguchi H, Wyckoff J, Condeelis J: Cell migration in tumors. Curr Opin Cell Biol 17: 559–564, 2005PubMedGoogle Scholar
  113. 113.
    Zigrino P, Loffek S, Mauch C: Tumor-stroma interactions: Their role in the control of tumor cell invasion. Biochimie 87: 321–328, 2005PubMedGoogle Scholar
  114. 114.
    Maquart FX, Bellon G, Pasco S, Monboisse JC: Matrikines in the regulation of extracellular matrix degradation. Biochimie 87: 353–360, 2005PubMedGoogle Scholar
  115. 115.
    Comoglio PM, Trusolino L: Cancer: The matrix is now in control. Nat Med 11: 1156–1159, 2005PubMedGoogle Scholar
  116. 116.
    Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, Leake D, Godden EL, Albertson DG, Nieto MA, Werb Z, Bissell MJ: Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 436: 123–127, 2005PubMedGoogle Scholar
  117. 117.
    Steeg PS: New insights into the tumor metastatic process revealed by gene expression profiling. Am J Pathol 166: 1291–1294, 2005PubMedGoogle Scholar
  118. 118.
    Steeg PS: Cancer biology: Emissaries set up new sites. Nature 438: 750–751, 2005PubMedGoogle Scholar
  119. 119.
    Clamp AR, Jayson GC: The clinical potential of antiangiogenic fragments of extracellular matrix proteins. Br J Cancer 93: 967–972, 2005PubMedGoogle Scholar
  120. 120.
    Zatovicova M, Sedlakova O, Svastova E, Ohradanova A, Ciampor F, Arribas J, Pastorek J, Pastorekova S: Ectodomain shedding of the hypoxia-induced carbonic anhydrase IX is a metalloprotease-dependent process regulated by TACE/ADAM17. Br J Cancer 93: 1267–1276, 2005PubMedGoogle Scholar
  121. 121.
    Tlsty TD, Coussens LM: Tumor stroma and regulation of cancer development. Annu Rev Pathol 1: 119–150, 2006PubMedGoogle Scholar
  122. 122.
    Rizvi NA, Humphrey JS, Ness EA, Johnson MD, Gupta E, Williams K, Daly DJ, Sonnichsen D, Conway D, Marshall J, Hurwitz H: A phase I study of oral BMS-275291, a Novel Nonhydroxamate Sheddase-Sparing Matrix Metalloproteinase Inhibitor, in Patients with Advanced or Metastatic Cancer. Clin Cancer Res 10: 1963–1970, 2004PubMedGoogle Scholar
  123. 123.
    Miller KD, Saphner TJ, Waterhouse DM, Chen TT, Rush-Taylor A, Sparano JA, Wolff AC, Cobleigh MA, Galbraith S, Sledge GW: A randomized phase II feasibility trial of BMS-275291 in patients with early stage breast cancer. Clin Cancer Res 10: 1971–1975, 2004PubMedGoogle Scholar
  124. 124.
    Leighl NB, Paz-Ares L, Douillard JY, Peschel C, Arnold A, Depierre A, Santoro A, Betticher DC, Gatzemeier U, Jassem J, Crawford J, Tu D, Bezjak A, Humphrey JS, Voi M, Galbraith S, Hann K, Seymour L, Shepherd FA: Randomized 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 23: 2831–2839, 2005PubMedGoogle Scholar
  125. 125.
    Gatto C, Rieppi M, Borsotti P, Innocenti S, Ceruti R, Drudis T, Scanziani E, Casazza AM, Taraboletti G, Giavazzi R: BAY 12-9566, a novel inhibitor of matrix metalloproteinases with antiangiogenic activity. Clin Cancer Res 5: 3603–3607, 1999PubMedGoogle Scholar
  126. 126.
    Heath EI, O'Reilly S, Humphrey R, Sundaresan P, Donehower RC, Sartorius S, Kennedy MJ, Armstrong DK, Carducci MA, Sorensen JM, Kumor K, Kennedy S, Grochow LB: Phase I trial of the matrix metalloproteinase inhibitor BAY12-9566 in patients with advanced solid tumors. Cancer Chemother Pharmacol 48: 269–274, 2001PubMedGoogle Scholar
  127. 127.
    Molina JR, Reid JM, Erlichman C, Sloan JA, Furth A, Safgren SL, Lathia CD, Alberts SR: A phase I and pharmacokinetic study of the selective, non-peptidic inhibitor of matrix metalloproteinase BAY 12-9566 in combination with etoposide and carboplatin. Anticancer Drugs 16: 997–1002, 2005PubMedGoogle Scholar
  128. 128.
    Hirte H, Stewart D, Goel R, Chouinard E, Huan S, Stafford S, Waterfield B, Matthews S, Lathia C, Schwartz B, Agarwal V, Humphrey R, Seymour AL: An NCIC-CTG phase I dose escalation pharmacokinetic study of the matrix metalloproteinase inhibitor BAY 12-9566 in combination with doxorubicin. Invest New Drugs 23: 437–443, 2005PubMedGoogle Scholar
  129. 129.
    Goel R, Chouinard E, Stewart DJ, Huan S, Hirte H, Stafford S, Waterfield B, Roach J, Lathia C, Agarwal V, Humphrey R, Walsh W, Matthews S, Seymour L: An NCIC CTG phase I/pharmacokinetic study of the matrix metalloproteinase and angiogenesis inhibitor BAY 12-9566 in combination with 5-fluorouracil/leucovorin. Invest New Drugs 23: 63–71, 2005PubMedGoogle Scholar
  130. 130.
    Lutz J, Yao Y, Song E, Antus B, Hamar P, Liu S, Heemann U: Inhibition of matrix metalloproteinases during chronic allograft nephropathy in rats. Transplantation 79: 655–661, 2005PubMedGoogle Scholar
  131. 131.
    Mannello F, Tonti GA, Bagnara GP, Papa S: Role and function of matrix metalloproteinases in the differentiation and biological characterization of mesenchymal stem cells. Stem Cells 24: In press, 2006Google Scholar
  132. 132.
    Hurst DR, Schwartz MA, Jin Y, Ghaffari MA, Kozarekar P, Cao J, Sang QX: Inhibition of enzyme activity of and cell-mediated substrate cleavage by membrane type 1 matrix metalloproteinase by newly developed mercaptosulphide inhibitors. Biochem J 392: 527–536, 2005PubMedGoogle Scholar
  133. 133.
    Fragai M, Nativi C, Richichi B, Venturi C: Design In silico, Synthesis and Binding Evaluation of a Carbohydrate-based Scaffold for Structurally Novel Inhibiitors of MMPs. ChemBioChem 6: 1345–1349, 2005PubMedGoogle Scholar
  134. 134.
    Lee M, Bernardo MM, Meroueh SO, Brown S, Fridman R, Mobashery S: Synthesis of chiral 2-(4-phenoxy phenylsulfonylmethyl)thiiranes as selective gelatinase inhibitors. Org Lett 7: 4463–4465, 2005PubMedGoogle Scholar
  135. 135.
    Parker MH, Ortwine DF, O'Brien PM, Lunney EA, Banotai CA, Mueller WT, McConnell P, Brouillette CG: Stereoselective binding of an enantiomeric pair of stromelysin-1 inhibitors caused by conformational entropy factors. Bioorg Med Chem Lett 10: 2427–2430, 2000PubMedGoogle Scholar
  136. 136.
    O'Brien PM, Ortwine DF, Pavlovsky AG, Picard JA, Sliskovic DR, Roth BD, Dyer RD, Johnson LL, Man CF, Hallak H: Structure-activity relationships and pharmacokinetic analysis for a series of potent, systemically available biphenylsulfonamide matrix metalloproteinase inhibitors. J Med Chem 43: 156–166, 2000PubMedGoogle Scholar
  137. 137.
    Pochetti G, Gavuzzo E, Campestre C, Agamennone M, Tortorella P, Consalvi V, Gallina C, Hiller O, Tschesche H, Tucker PA, Mazza F: Structural Insight into the Stereoselective Inhibition of MMP-8 by Enantiomeric Sulfonamide Phosphonates. J Med Chem 49: 923–931, 2006PubMedGoogle Scholar
  138. 138.
    Ikejiri M, Bernardo MM, Meroueh SO, Brown S, Chang M, Fridman R, Mobashery S: Design, synthesis, and evaluation of a mechanism-based inhibitor for gelatinase A. J Org Chem 70: 5709–5712, 2005PubMedGoogle Scholar
  139. 139.
    Ikejiri M, Bernardo MM, Bonfil RD, Toth M, Chang M, Fridman R, Mobashery S: Potent Mechanism-based Inhibitors for Matrix Metalloproteinases. J Biol Chem 280: 33992–34002, 2005PubMedGoogle Scholar
  140. 140.
    Solomon A, Rosenblum G, Gonzales PE, Leonard JD, Mobashery S, Milla ME, Sagi I: Pronounced diversity in electronic and chemical properties between the catalytic zinc sites of tumor necrosis factor-alpha-converting enzyme and matrix metalloproteinases despite their high structural similarity. J Biol Chem 279: 31646–31654, 2004PubMedGoogle Scholar
  141. 141.
    Kruger A, Arlt MJ, Gerg M, Kopitz C, Bernardo MM, Chang M, Mobashery S, Fridman R: Antimetastatic activity of a novel mechanism-based gelatinase inhibitor. Cancer Res 65: 3523–3526, 2005PubMedGoogle Scholar
  142. 142.
    Bonfil RD, Sabbota A, Nabha S, Bernardo MM, Dong Z, Meng H, Yamamoto H, Chinni SR, Lim I, Chang M, Filetti LC, Mobashery S, Cher ML, Fridman R: Inhibition of human prostate cancer growth, osteolysis and angiogenesis in a bone metastasis model by a novel mechanism-based selective gelatinase inhibitor. Int J Cancer 118: 2721–2726, 2006PubMedGoogle Scholar
  143. 143.
    Gu Z, Cui J, Brown S, Fridman R, Mobashery S, Strongin AY, Lipton SA: A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia. J Neurosci 25: 6401–6408, 2005PubMedGoogle Scholar
  144. 144.
    Grams F, Brandstetter H, D'Alo S, Geppert D, Krell HW, Leinert H, Livi V, Menta E, Oliva A, Zimmermann G: Pyrimidine-2,4,6-Triones: A new effective and selective class of matrix metalloproteinase inhibitors. Biol Chem 382: 1277–1285, 2001PubMedGoogle Scholar
  145. 145.
    Genter MB, Warner BM, Krell HW, Bolon B: Reduction of alachlor-induced olfactory mucosal neoplasms by the matrix metalloproteinase inhibitor Ro 28-2653. Toxicol Pathol 33: 593–599, 2005PubMedGoogle Scholar
  146. 146.
    Lein M, Jung K, Ortel B, Stephan C, Rothaug W, Juchem R, Johannsen M, Deger S, Schnorr D, Loening S, Krell HW: The new synthetic matrix metalloproteinase inhibitor (Roche 28-2653) reduces tumor growth and prolongs survival in a prostate cancer standard rat model. Oncogene 21: 2089–2096, 2002PubMedGoogle Scholar
  147. 147.
    Mangoldt D, Sinn B, Lein M, Krell HW, Schnorr D, Loening SA, Jung K: The novel synthetic inhibitor of matrix metalloproteinases Ro 28–2653 induces apoptosis in Dunning tumor cells. Apoptosis 7: 217–220, 2002PubMedGoogle Scholar
  148. 148.
    Jung K, Krell HW, Ortel B, Hasan T, Romer A, Schnorr D, Loening SA, Lein M: Plasma matrix metalloproteinase 9 as biomarker of prostate cancer progression in Dunning (Copenhagen) rats. Prostate 54: 206–211, 2003PubMedGoogle Scholar
  149. 149.
    Maquoi E, Sounni NE, Devy L, Olivier F, Frankenne F, Krell HW, Grams F, Foidart JM, Noel A: Anti-invasive, antitumoral, and antiangiogenic efficacy of a pyrimidine-2,4,6-trione derivative, an orally active and selective matrix metalloproteinases inhibitor. Clin Cancer Res 10: 4038–4047, 2004PubMedGoogle Scholar
  150. 150.
    Kruse MN, Becker C, Lottaz D, Kohler D, Yiallouros I, Krell HW, Sterchi EE, Stocker W: Human meprin alpha and beta homo-oligomers: cleavage of basement membrane proteins and sensitivity to metalloprotease inhibitors. Biochem J 378: 383–389, 2004PubMedGoogle Scholar
  151. 151.
    Demeulemeester D, Collen D, Lijnen HR: Effect of matrix metalloproteinase inhibition on adipose tissue development. Biochem Biophys Res Commun 329: 105–110, 2005PubMedGoogle Scholar
  152. 152.
    Brandstetter H, Grams F, Glitz D, Lang A, Huber R, Bode W, Krell HW, Engh RA: The 1.8-A Crystal Structure of a Matrix Metalloproteinase 8-Barbiturate Inhibitor Complex Reveals a Previously Unobserved Mechanism for Collagenase Substrate Recognition. J Biol Chem 276: 17405–17412, 2001PubMedGoogle Scholar
  153. 153.
    Bertini I, Calderone V, Cosenza M, Fragai M, Lee YM, Luchinat C, Mangani S, Terni B, Turano P: Conformational variability of matrix metalloproteinases: Beyond a single 3D structure. Proc Natl Acad Sci USA 102: 5334–5339, 2005PubMedGoogle Scholar
  154. 154.
    Engel CK, Pirard B, Schimanski S, Kirsch R, Habermann J, Klingler O, Schlotte V, Weithmann KU, Wendt KU: Structural Basis for the Highly Selective Inhibition of MMP-13. Chem Biol 12: 181–189, 2005PubMedGoogle Scholar
  155. 155.
    Kim SH, Pudzianowski AT, Leavitt KJ, Barbosa J, McDonnell PA, Metzler WJ, Rankin BM, Liu R, Vaccaro W, Pitts W: Structure-based design of potent and selective inhibitors of collagenase-3 (MMP-13). Bioorg Med Chem Lett 15: 1101–1106, 2005PubMedGoogle Scholar
  156. 156.
    Dunten P, Kammlott U, Crowther R, Levin W, Foley LH, Wang P, Palermo R: X-ray structure of a novel MMP inhibitor complexed to stromelysin. Protein Sci 10: 923–926, 2001PubMedGoogle Scholar
  157. 157.
    Blagg JA, Noe MC, Wolf-Gouveia LA, Reiter LA, Laird ER, Chang SP, Danley DE, Downs JT, Elliott NC, Eskra JD, Griffiths RJ, Hardink JR, Haugeto AI, Jones CS, Liras JL, Lopresti-Morrow LL, Mitchell PG, Pandit J, Robinson RP, Subramanyam C, Vaughn-Bowser ML, Yocum SA: Potent pyrimidinetrione-based inhibitors of MMP-13 with enhanced selectivity over MMP-14. Bioorg Med Chem Lett 15: 1807–1810, 2005PubMedGoogle Scholar
  158. 158.
    Breyholz HJ, Schafers M, Wagner S, Holtke C, Faust A, Rabeneck H, Levkau B, Schober O, Kopka K: C-5-disubstituted barbiturates as potential molecular probes for noninvasive matrix metalloproteinase imaging. J Med Chem 48: 3400–3409, 2005PubMedGoogle Scholar
  159. 159.
    Kopka K, Breyholz HJ, Wagner S, Law MP, Riemann B, Schroer S, Trub M, Guilbert B, Levkau B, Schober O, Schafers M: Synthesis and preliminary biological evaluation of new radioiodinated MMP inhibitors for imaging MMP activity in vivo. Nucl Med Biol 31: 257–267, 2004PubMedGoogle Scholar
  160. 160.
    Schafers M, Riemann B, Kopka K, Breyholz HJ, Wagner S, Schafers KP, Law M, Schober O, Levkau B: Scintigraphic imaging of matrix metalloproteinase activity in the arterial wall in vivo. Circulation 109: 2554–2559, 2004PubMedGoogle Scholar
  161. 161.
    Anonymous: MMP-13 Inhibitors. Aventis Res. & Tech. WO2004060874 & WO2004060883. Expert Opin Ther Patents 15: 237–241, 2005Google Scholar
  162. 162.
    Puerta DT, Mongan J, Tran BL, McCammon JA, Cohen SM: Potent, selective pyrone-based inhibitors of stromelysin-1. J Am Chem Soc 127: 14148–14149, 2005PubMedGoogle Scholar
  163. 163.
    Puerta DT, Morgan J, Tran BL, McCammon JA, Cohen SM: From Model Complexes to Metalloprotein Inhibition: A Synergistic Approach to Structure-Based Drug Discovery. Angew Chem Int Ed 42: 3772–3775, 2003Google Scholar
  164. 164.
    He H, Puerta DT, Cohen SM, Rodgers KR: Structural and spectroscopic study of reactions between chelating zinc-binding groups and mimics of the matrix metalloproteinase and disintegrin metalloprotease catalytic sites: the coordination chemistry of metalloprotease inhibition. Inorg Chem 44: 7431–7442, 2005PubMedGoogle Scholar
  165. 165.
    Onaran MB, Comeau AB, Seto CT: Squaric acid-based peptidic inhibitors of MMP-1. J Org Chem 70: 10792–10802, 2005PubMedGoogle Scholar
  166. 166.
    Juers DH, Kim J, Matthews BW, Sieburth SM: Structural Analysis of Silanediols as Transition-State-Analogue Inhibitors of the Benchmark Metalloprotease Thermolysin. Biochemistry 44: 16524–16528, 2005PubMedGoogle Scholar
  167. 167.
    Sieburth SM, Chen CA: Silanediol Protease Inhibitors: From Conception to Validation. Eur J Org Chem: 311–322, 2006Google Scholar
  168. 168.
    Dive V, Georgiadis D, Matziari M, Makaritis A, Beau F, Cuniasse P, Yiotakis A: Phosphinic peptides as zinc metalloproteinase inhibitors. Cell Mol Life Sci 61: 2010–2019, 2004PubMedGoogle Scholar
  169. 169.
    Reiter LA, Mitchell PG, Martinelli GJ, Lopresti-Morrow LL, Yocum SA, Eskra JD: Phosphinic acid-based MMP-13 inhibitors that spare MMP-1 and MMP-3. Bioorg Med Chem Lett 13: 2331–2336, 2003PubMedGoogle Scholar
  170. 170.
    Gall AL, Ruff M, Kannan R, Cuniasse P, Yiotakis A, Dive V, Rio MC, Basset P, Moras D: Crystal structure of the stromelysin-3 (MMP-11) catalytic domain complexed with a phosphinic inhibitor mimicking the transition-state. J Mol Biol 307: 577–586, 2001PubMedGoogle Scholar
  171. 171.
    Matziari M, Beau F, Cuniasse P, Dive V, Yiotakis A: Evaluation of P1'-diversified phosphinic peptides leads to the development of highly selective inhibitors of MMP-11. J Med Chem 47: 325–336, 2004PubMedGoogle Scholar
  172. 172.
    Dive V, Andarawewa KL, Boulay A, Matziari M, Beau F, Guerin E, Rousseau B, Yiotakis A, Rio MC: Dosing and scheduling influence the antitumor efficacy of a phosphinic peptide inhibitor of matrix metalloproteinases. Int J Cancer 113: 775–781, 2005PubMedGoogle Scholar
  173. 173.
    Andarawewa KL, Motrescu ER, Chenard MP, Gansmuller A, Stoll I, Tomasetto C, Rio MC: Stromelysin-3 is a potent negative regulator of adipogenesis participating to cancer cell-adipocyte interaction/crosstalk at the tumor invasive front. Cancer Res 65: 10862–10871, 2005PubMedGoogle Scholar
  174. 174.
    Andarawewa KL, Boulay A, Masson R, Mathelin C, Stoll I, Tomasetto C, Chenard MP, Gintz M, Bellocq JP, Rio M: Dual stromelysin-3 function during natural mouse mammary tumor virus-ras tumor progression. Cancer Res 63: 5844–5849, 2003PubMedGoogle Scholar
  175. 175.
    Coussens LM, Fingleton B, Matrisian LM: Matrix metalloproteinase inhibitors and cancer: Trials and tribulations. Science 295: 2387–2392, 2002PubMedGoogle Scholar
  176. 176.
    DeClerck YA, Mercurio AM, Stack MS, Chapman HA, Zutter MM, Muschel RJ, Raz A, Matrisian LM, Sloane BF, Noel A, Hendrix MJ, Coussens L, Padarathsingh M: Proteases, extracellular matrix, and cancer: A workshop of the path B study section. Am J Pathol 164: 1131–1139, 2004PubMedGoogle Scholar
  177. 177.
    Breuer E, Katz Y, Hadar R, Reich R: Carbamoylphosphonate MMP inhibitors. Part 4: The influence of chirality and geometrical isomerism on the potency and selectivity of inhibition. Tetrahedron: Asymmetry 15: 2415, 2004Google Scholar
  178. 178.
    Breuer E, Salomon CJ, Katz Y, Chen W, Lu S, Roschenthaler GV, Hadar R, Reich R: Carbamoylphosphonates, a new class of in vivo active matrix metalloproteinase inhibitors. 1. Alkyl- and cycloalkylcarbamoylphosphonic acids. J Med Chem 47: 2826–2832, 2004PubMedGoogle Scholar
  179. 179.
    Agamennone M, Campestre C, Preziuso S, Consalvi V, Crucianelli M, Mazza F, Politi V, Ragno R, Tortorella P, Gallina C: Synthesis and evaluation of new tripeptide phosphonate inhibitors of MMP-8 and MMP-2. Eur J Med Chem 40: 271–279, 2005PubMedGoogle Scholar
  180. 180.
    Bianchini G, Aschi M, Cavicchio G, Crucianelli M, Preziuso S, Gallina C, Nastari A, Gavuzzo E, Mazza F: Design, modelling, synthesis and biological evaluation of peptidomimetic phosphinates as inhibitors of matrix metalloproteinases MMP-2 and MMP-8. Bioorg Med Chem 13: 4740–4749, 2005PubMedGoogle Scholar
  181. 181.
    Clezardin P, Fournier P, Boissier S, Peyruchaud O: In vitro and in vivo antitumor effects of bisphosphonates. Curr Med Chem 10: 173–180, 2003PubMedGoogle Scholar
  182. 182.
    Conte P, Coleman R: Bisphosphonates in the treatment of skeletal metastases. Semin Oncol 31: 59–63, 2004PubMedGoogle Scholar
  183. 183.
    Perry CM, Figgitt DP: Zoledronic acid: A review of its use in patients with advanced cancer. Drugs 64: 1197–1211, 2004PubMedGoogle Scholar
  184. 184.
    Rosen LS, Gordon D, Tchekmedyian NS, Yanagihara R, Hirsh V, Krzakowski M, Pawlicki M, De Souza P, Zheng M, Urbanowitz G, Reitsma D, Seaman J: Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: A randomized, Phase III, double-blind, placebo-controlled trial. Cancer 100: 2613–2621, 2004PubMedGoogle Scholar
  185. 185.
    Saba N, Khuri F: The role of bisphosphonates in the management of advanced cancer with a focus on non-small-cell lung cancer. Part 1: Mechanisms of action, role of biomarkers and preclinical applications. Oncology 68: 10–17, 2005PubMedGoogle Scholar
  186. 186.
    Ural AU, Avcu F: Evolving therapeutic role of bisphosphonates in multiple myeloma. Br J Cancer 93: 267–268; author reply 269, 2005PubMedGoogle Scholar
  187. 187.
    Clezardin P, Ebetino FH, Fournier PG: Bisphosphonates and cancer-induced bone disease: Beyond their antiresorptive activity. Cancer Res 65: 4971–4974, 2005PubMedGoogle Scholar
  188. 188.
    Clezardin P: Anti-tumour activity of zoledronic acid. Cancer Treat Rev 31 Suppl 3: 1–8, 2005PubMedGoogle Scholar
  189. 189.
    Coleman RE: Bisphosphonates in breast cancer. Ann Oncol 16: 687–695, 2005PubMedGoogle Scholar
  190. 190.
    Boissier S, Ferreras M, Peyruchaud O, Magnetto S, Ebetino FH, Colombel M, Delmas P, Delaisse JM, Clezardin P: Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res 60: 2949–2954, 2000PubMedGoogle Scholar
  191. 191.
    Heikkila P, Teronen O, Moilanen M, Konttinen YT, Hanemaaijer R, Laitinen M, Maisi P, van der Pluijm G, Bartlett JD, Salo T, Sorsa T: Bisphosphonates inhibit stromelysin-1 (MMP-3), matrix metalloelastase (MMP-12), collagenase-3 (MMP–13) and enamelysin (MMP-20), but not urokinase-type plasminogen activator, and diminish invasion and migration of human malignant and endothelial cell lines. Anticancer Drugs 13: 245–254, 2002PubMedGoogle Scholar
  192. 192.
    Heikkila P, Teronen O, Hirn MY, Sorsa T, Tervahartiala T, Salo T, Konttinen YT, Halttunen T, Moilanen M, Hanemaaijer R, Laitinen M: Inhibition of matrix metalloproteinase-14 in osteosarcoma cells by clodronate. J Surg Res 111: 45–52, 2003PubMedGoogle Scholar
  193. 193.
    Corso A, Ferretti E, Lunghi M, Zappasodi P, Mangiacavalli S, De Amici M, Rusconi C, Varettoni M, Lazzarino M: Zoledronic acid down-regulates adhesion molecules of bone marrow stromal cells in multiple myeloma: a possible mechanism for its antitumor effect. Cancer 104: 118–125, 2005PubMedGoogle Scholar
  194. 194.
    Corso A, Ferretti E, Lazzarino M: Zoledronic acid exerts its antitumor effect in multiple myeloma interfering with the bone marrow microenvironment. Hematology 10: 215–224, 2005PubMedGoogle Scholar
  195. 195.
    Ferretti G, Fabi A, Carlini P, Papaldo P, Cordiali Fei P, Di Cosimo S, Salesi N, Giannarelli D, Alimonti A, Di Cocco B, D'Agosto G, Bordignon V, Trento E, Cognetti F: Zoledronic-acid-induced circulating level modifications of angiogenic factors, metalloproteinases and proinflammatory cytokines in metastatic breast cancer patients. Oncology 69: 35–43, 2005PubMedGoogle Scholar
  196. 196.
    Giraudo E, Inoue M, Hanahan D: An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J Clin Invest 114: 623–633, 2004PubMedGoogle Scholar
  197. 197.
    Fingleton B: CMT-3. CollaGenex. Curr Opin Investig Drugs 4: 1460–1467, 2003PubMedGoogle Scholar
  198. 198.
    Acharya MR, Venitz J, Figg WD, Sparreboom A: Chemically modified tetracyclines as inhibitors of matrix metalloproteinases. Drug Resist Updat 7: 195–208, 2004PubMedGoogle Scholar
  199. 199.
    Kivela-Rajamaki M, Maisi P, Srinivas R, Tervahartiala T, Teronen O, Husa V, Salo T, Sorsa T: Levels and molecular forms of MMP-7 (matrilysin-1) and MMP-8 (collagenase-2) in diseased human peri-implant sulcular fluid. J Periodontal Res 38: 583–590, 2003PubMedGoogle Scholar
  200. 200.
    Blum D, Chtarto A, Tenenbaum L, Brotchi J, Levivier M: Clinical potential of minocycline for neurodegenerative disorders. Neurobiol Dis 17: 359–366, 2004PubMedGoogle Scholar
  201. 201.
    Diguet E, Gross CE, Tison F, Bezard E: Rise and fall of minocycline in neuroprotection: need to promote publication of negative results. Exp Neurol 189: 1–4, 2004PubMedGoogle Scholar
  202. 202.
    Domercq M, Matute C: Neuroprotection by tetracyclines. Trends Pharmacol Sci 25: 609–612, 2004PubMedGoogle Scholar
  203. 203.
    Yong VW, Wells J, Giuliani F, Casha S, Power C, Metz LM: The promise of minocycline in neurology. Lancet Neurol 3: 744–751, 2004PubMedGoogle Scholar
  204. 204.
    Zink MC, Uhrlaub J, DeWitt J, Voelker T, Bullock B, Mankowski J, Tarwater P, Clements J, Barber S: Neuroprotective and anti-human immunodeficiency virus activity of minocycline. JAMA 293: 2003–2011, 2005PubMedGoogle Scholar
  205. 205.
    Stirling DP, Koochesfahani KM, Steeves JD, Tetzlaff W: Minocycline as a neuroprotective agent. Neuroscientist 11: 308–322, 2005PubMedGoogle Scholar
  206. 206.
    Garcia RA, Pantazatos DP, Gessner CR, Go KV, Woods VL, Villarreal FJ: Molecular interactions between matrilysin and the matrix metalloproteinase inhibitor doxycycline investigated by deuterium exchange mass spectrometry. Mol Pharmacol 67: 1128–1136, 2005PubMedGoogle Scholar
  207. 207.
    Gu Y, Lee HM, Golub LM, Sorsa T, Konttinen YT, Simon S: Inhibition of breast cancer cell extracellular matrix degradative activity by chemically modified tetracyclines. Ann Med 37: 450–460, 2005PubMedGoogle Scholar
  208. 208.
    Koistinaho M, Malm TM, Kettunen MI, Goldsteins G, Starckx S, Kauppinen RA, Opdenakker G, Koistinaho J: Minocycline protects against permanent cerebral ischemia in wild type but not in matrix metalloprotease-9-deficient mice. J. Cereb. Blood Flow Metab 25: 460–467, 2005Google Scholar
  209. 209.
    Sandler C, Ekokoski E, Lindstedt K, Vainio P, Finel M, Sorsa T, Kovanen P, Golub L, Eklund K: Chemically modified tetracycline (CMT)-3 inhibits histamine release and cytokine production in mast cells: Possible involvement of protein kinase C. Inflamm Res 54: 304–312, 2005PubMedGoogle Scholar
  210. 210.
    Lee CZ, Yao JS, Huang Y, Zhai W, Liu W, Guglielmo BJ, Lin E, Yang GY, Young WL: Dose-response effect of tetracyclines on cerebral matrix metalloproteinase-9 after vascular endothelial growth factor hyperstimulation. J Cereb Blood Flow Metab 26: In press, 2006Google Scholar
  211. 211.
    Onoda T, Ono T, Dhar D, Yamanoi A, Nagasue N: Tetracycline analogues (doxycycline and COL-3) induce caspase-dependent and -independent apoptosis in human colon cancer cells. Int J Cancer 118: 1309–1315, 2006PubMedGoogle Scholar
  212. 212.
    Salo T, Soini Y, Oiva J, Kariylitalo, Nissinen A, Biancari F, Juvonen T, Satta J: Chemically modified tetracyclines (CMT-3 and CMT-8) enable control of the pathologic remodellation of human aortic valve stenosis via MMP-9 and VEGF inhibition. Int J Cardiol 107: In press, 2006Google Scholar
  213. 213.
    Lertvorachon J, Kim JP, Soldatov DV, Boyd J, Roman G, Cho SJ, Popek T, Jung YS, Lau PCK, Konishi Y: 1,12-Substituted tetracyclines as antioxidant agents. Bioorg Med Chem 13: 4627–4637, 2005PubMedGoogle Scholar
  214. 214.
    Savaraj N, Wei Y, Unate H, Liu PM, Wu CJ, Wangpaichitr M, Xia D, Xu HJ, Hu SX, Tien Kuo M: Redox regulation of matrix metalloproteinase gene family in small cell lung cancer cells. Free Radic Res 39: 373–381, 2005PubMedGoogle Scholar
  215. 215.
    Steinberg J, Halter J, Schiller H, Gatto L, Carney D, Lee HM, Golub L, Nieman G: Chemically modified tetracycline prevents the development of septic shock and acute respiratory distress syndrome in a clinically applicable porcine model. Shock 24: 348–356, 2005PubMedGoogle Scholar
  216. 216.
    Kaliski A, Maggiorella L, Cengal KA, Mathe D, Rouffiac V, Opolon P, Lassau N, Bourhis J, Deutsch E: Angiogenesis and tumor growth inhibition by a MMP inhibitor targeting radiation-induced invasion. Mol Cancer Ther 4: 1717–1728, 2005PubMedGoogle Scholar
  217. 217.
    Syed S, Takimoto C, Hidalgo M, Rizzo J, Kuhn JG, Hammond LA, Schwartz G, Tolcher A, Patnaik A, Eckhardt SG, Rowinsky EK: A phase I and pharmacokinetic study of Col-3 (Metastat), an oral tetracycline derivative with potent matrix metalloproteinase and antitumor properties. Clin Cancer Res 10: 6512–6521, 2004PubMedGoogle Scholar
  218. 218.
    Brandt KD, Mazzuca, SA: The randomized clinical trial of doxycycline in knee osteoarthritis: Comment on the editorial by Dieppe. Arthritis Rheum 54: 684, 2006PubMedGoogle Scholar
  219. 219.
    Bukowski RM: AE-941, a multifunctional antiangiogenic compound: trials in renal cell carcinoma. Expert Opin Investig Drugs 12:1403–1411, 2003PubMedGoogle Scholar
  220. 220.
    Dredge K: AE-941 (AEterna). Curr Opin Investig Drugs 5: 668–677, 2004PubMedGoogle Scholar
  221. 221.
    Finkelstein JB: Sharks do get cancer: Few surprises in cartilage research. J Natl Cancer Inst 97: 1562–1563, 2005PubMedCrossRefGoogle Scholar
  222. 222.
    Beliveau R, Gingras D, Kruger EA, Lamy S, Sirois P, Simard B, Sirois MG, Tranqui L, Baffert F, Beaulieu E, Dimitriadou V, Pepin MC, Courjal F, Ricard I, Poyet P, Falardeau P, Figg WD, Dupont E: The antiangiogenic agent neovastat (AE-941) inhibits VEGF-mediated biological effects. Clin Cancer Res 8: 1242–1250, 2002PubMedGoogle Scholar
  223. 223.
    Rini BI, Small EJ: Biology and Clinical Development of VEGF-targeted Therapy in Renal Cell Carcinoma. J Clin Oncol 23: 1028–1043, 2005PubMedGoogle Scholar
  224. 224.
    Herbst RS, Onn A, Sandler A: Angiogenesis and Lung Cancer: Prognostic and therapeutic implications. J Clin Oncol 23: 3243–3256, 2005PubMedGoogle Scholar
  225. 225.
    Boivin D, Provencal M, Gendron S, Ratel D, Demeule M, Gingras D, Beliveau R: Purification and characterization of a stimulator of plasmin generation from the antiangiogenic agent Neovastat: Identification as immunoglobulin kappa light chain. Arch Biochem Biophys 431: 197–206, 2004PubMedGoogle Scholar
  226. 226.
    Gingras D, Boivin D, Deckers C, Gendron S, Barthomeuf C, Beliveau R: Neovastat–a novel antiangiogenic drug for cancer therapy. Anticancer Drugs 14: 91–96, 2003PubMedGoogle Scholar
  227. 227.
    Gingras D, Batist G, Beliveau R: AE-941 (Neovastat): A novel multifunctional antiangiogenic compound. Expert Rev Anticancer Ther 1: 341–347, 2001PubMedGoogle Scholar
  228. 228.
    Lee SY, Paik SY, Chung SM: Neovastat (AE-941) inhibits the airway inflammation and hyperresponsiveness in a murine model of asthma. J Microbiol 43: 11–16, 2005PubMedGoogle Scholar
  229. 229.
    Latreille J, Batist G, Laberge F, Champagne P, Croteau D, Falardeau P, Levinton C, Hariton C, Evans W, Dupont E: Phase I/II trial of the safety and efficacy of AE-941 (Neovastat) in the treatment of non-small-cell lung cancer. Clin Lung Cancer 4: 231–236, 2003PubMedCrossRefGoogle Scholar
  230. 230.
    Lu C, Komacki R, Herbst RS, Evans WK, Lee JJ, Truong M, Moore CA, Choy H, Bleyer A, Fisch MJ: A phase III study of AE-941 with induction chemotherapy and concomitant chemoradiotherapy for stage III NSCLC (NCI T99-0046, RTOG 02-70, MDA 99-303): An interim report of toxicity and response. J Clin Oncol 23 (16S Supplement): Abstract 7144, 2005Google Scholar

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© Springer Science + Business Media, LLC 2006

Authors and Affiliations

  1. 1.Department of Chemistry and BiochemistryUniversity of Notre DameNotre Dame

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