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Matrix Metalloproteinase Inhibitors

A Critical Appraisal of Design Principles and Proposed Therapeutic Utility

Abstract

Matrix metalloproteinases (MMPs) play an important role in tissue remodelling associated with various physiological and pathological processes, such as morphogenesis, angiogenesis, tissue repair, arthritis, chronic heart failure, chronic obstructive pulmonary disease, chronic inflammation and cancer metastasis. As a result, MMPs are considered to be viable drug targets in the therapy of these diseases. Despite the high therapeutic potential of MMP inhibitors (MMPIs), all clinical trials have failed to date, except for doxycycline for periodontal disease. This can be attributed to (i) poor selectivity of the MMPIs, (ii) poor target validation for the targeted therapy and (iii) poorly defined predictive preclinical animal models for safety and efficacy. Lessons from previous failures, such as recent discoveries of oxidative/nitrosative activation and phosphorylation of MMPs, as well as novel non-matrix related intra- and extracellular targets of MMP, give new hope for MMPI development for both chronic and acute diseases. In this article we critically review the major structural determinants of the selectivity and the milestones of past design efforts of MMPIs where 2-/3-dimensional structure-based methods were intensively applied. We also analyse the in vitro screening and preclinical/clinical pharmacology approaches, with particular emphasis on drawing conclusions on how to overcome efficacy and safety problems through better target validation and design of preclinical studies.

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References

  1. Gross J, Lapiere CM. Collagenolytic activity in amphibian tissues: a tissue culture assay. Proc Natl Acad Sci U S A 1962; 48: 1014–22

    PubMed  Article  CAS  Google Scholar 

  2. Li NG, Shi ZH, Tang YP, et al. Selective matrix metalloproteinase inhibitors for cancer. Curr Med Chem 2009; 16: 3805–27

    Article  CAS  Google Scholar 

  3. Peterson JT. The importance of estimating the therapeutic index in the development of matrix metalloproteinase inhibitors. Cardiovasc Res 2006; 69: 677–87

    PubMed  Article  CAS  Google Scholar 

  4. Johnson AR, Pavlovsky AG, Ortwine DF, et al. Discovery and characterization of a novel inhibitor of matrix metalloprotease-13 that reduces cartilage damage in vivo without joint fibroplasia side effects. J Biol Chem 2007; 282: 27781–91

    PubMed  Article  CAS  Google Scholar 

  5. Renkiewicz R, Qiu L, Lesch C, et al. Broad-spectrum matrix metalloproteinase inhibitor marimastat-induced musculoskeletal side effects in rats. Arthritis Rheum 2003; 48: 1742–9

    PubMed  Article  CAS  Google Scholar 

  6. Dorman G, Kocsis-Szommer K, Spadoni C, et al. MMP inhibitors in cardiac diseases: an update. Recent Pat Cardiovasc Drug Discov 2007; 2: 186–94

    PubMed  Article  CAS  Google Scholar 

  7. Chow AK, Cena J, Schulz R. Acute actions and novel targets of matrix metalloproteinases in the heart and vasculature. Br J Pharmacol 2007; 152: 189–205

    PubMed  Article  CAS  Google Scholar 

  8. Aureli L, Gioia M, Cerbara I, et al. Structural bases for substrate and inhibitor recognition by matrix metalloproteinases. Curr Med Chem 2008; 15: 2192–222

    PubMed  Article  CAS  Google Scholar 

  9. Yiotakis A, Dive V. Third-generation MMP inhibitors: recent advances in the development of highly selective inhibitors. In: Edwards D, Høyer-Hansen G, Blasi F, et al., editors. The cancer degradome: proteases and cancer biology. New York: Springer Science + Business Media, 2008: 811–25

    Chapter  Google Scholar 

  10. Netzel-Arnett S, Sang QX, Moore WG, et al. Comparative sequence specificities of human 72- and 92-kDa gelatinases (type IV collagenases) and PUMP (matrilysin). Biochemistry 1993; 32: 6427–32

    PubMed  Article  CAS  Google Scholar 

  11. Lukacova V, Zhang Y, Mackov M, et al. Similarity of binding sites of human matrix metalloproteinases. J Biol Chem 2004; 279(14): 14194–200

    PubMed  Article  CAS  Google Scholar 

  12. Pirard B. Insight into the structural determinants for selective inhibition of matrix metalloproteinases. Drug Discov Today 2007 Aug; 12(15–16): 640–6

    PubMed  Article  CAS  Google Scholar 

  13. Pirard B, Matter H. Matrix metalloproteinase target family landscape: a chemometrical approach to ligand selectivity based on protein binding site analysis. J Med Chem 2006; 49(1): 51–69

    PubMed  Article  CAS  Google Scholar 

  14. Lukacova V, Khandelwal A, Zhang Y, et al. Selectivity and affinity of matrix metalloproteinase inhibitors. In: Naidoo KJ, Brady J, Field MJ, et al., editors. Modelling molecular structure and reactivity in biological systems. London: Royal Society of Chemistry, 2006: 193–205

    Google Scholar 

  15. Pochetti G, Montanari R, Gege C, et al. Extra binding region induced by non-zinc chelating inhibitors into the S(1)t’ subsite of matrix metalloproteinase 8 (MMP-8). J Med Chem 2009; 52(4): 1040–9

    PubMed  Article  CAS  Google Scholar 

  16. Engel CK, Pirard B, Schimanski S, et al. Structural basis for the highly selective inhibition of MMP-13. Chem Biol 2005 Feb; 12(2): 181–9

    PubMed  Article  CAS  Google Scholar 

  17. Papp A, Szommer T, Barna L, et al. Enhanced hit-to-lead process using bioanalogous lead evolution and chemogenomics: application in designing selective matrix metalloprotease inhibitors. Expert Opin Drug Discov 2007; 2(5): 1–17

    Article  Google Scholar 

  18. Verma RP, Hansch C. Matrix metalloproteinases (MMPs): chemical-biological functions and (Q)SARs. Bioorg Med Chem 2007; 15: 2223–68

    PubMed  Article  CAS  Google Scholar 

  19. Fisher JF, Mobashery S. Recent advances in MMP inhibitor design. Cancer Metastasis Rev 2006 Mar; 25(1): 115–36

    PubMed  Article  CAS  Google Scholar 

  20. Jacobsen FE, Lewis JA, Cohen SM. The design of inhibitors for medicinally relevant metalloproteins. Chem Med Chem 2007 Feb; 2(2): 152–71

    PubMed  CAS  Google Scholar 

  21. Hajduk PJ, Sheppard G, Nettesheim D, et al. Discovery of potent nonpeptide inhibitors of stromelysin using SAR by NMR. J Am Chem Soc 1997; 119: 5818–27

    Article  CAS  Google Scholar 

  22. Nordström H, Gossas T, Hämäläinen M, et al. Identification of MMP-12 inhibitors by using biosensor-based screening of a fragment library. J Med Chem 2008 Jun 26; 51(12): 3449–59

    PubMed  Article  Google Scholar 

  23. Takahashi K, Ikura M, Habashita H, et al. Novel matrix metalloproteinase inhibitors: generation of lead compounds by the in silico fragment-based approach. Bioorg Med Chem 2005 Jul 15; 13(14): 4527–43

    PubMed  Article  CAS  Google Scholar 

  24. Puerta DT, Griffin MO, Lewis JA, et al. Heterocyclic zincbinding groups for use in next-generation matrix metalloproteinase inhibitors: potency, toxicity, and reactivity. J Biol Inorg Chem 2006 Mar; 11(2): 131–8

    PubMed  Article  CAS  Google Scholar 

  25. Jacobsen FE, Lewis JA, Cohen SM. A new role for old ligands: discerning chelators for zinc metalloproteinases. J Am Chem Soc 2006 Mar 15; 128(10): 3156–7

    PubMed  Article  CAS  Google Scholar 

  26. Agrawal A, Romero-Perez D, Jacobsen JA, et al. Zincbinding groups modulate selective inhibition of MMPs. Chem Med Chem 2008 May; 3(5): 812–20

    PubMed  CAS  Google Scholar 

  27. Marimastat: BB 2516, TA 2516. Drugs R D 2003; 4 (3): 198-203

  28. Winding B, NicAmhlaoibh R, Misander H, et al. Synthetic matrix metalloproteinase inhibitors inhibit growth of established breast cancer osteolytic lesions and prolong survival in mice. Clin Cancer Res 2002 Jun; 8: 1932–9

    PubMed  CAS  Google Scholar 

  29. De B, Natchus MG, Cheng M, et al. The next generation of MMP inhibitors: design and synthesis. Ann N Y Acad Sci 1999; 878: 40–60

    PubMed  Article  CAS  Google Scholar 

  30. Scatena R. Prinomastat, a hydroxamate-based matrix metalloproteinase inhibitor: a novel pharmacological approach for tissue remodelling-related diseases. Expert Opin Investig Drugs 2000 Sep; 9(9): 2159–65

    PubMed  Article  CAS  Google Scholar 

  31. Johnson JL, Fritsche-Danielson R, Behrendt M, et al. Effect of broad-spectrum matrix metalloproteinase inhibition on atherosclerotic plaque stability. Cardiovasc Res 2006 Aug 1; 71(3): 586–95

    PubMed  Article  CAS  Google Scholar 

  32. Hu Y, Xiang JS, DiGrandi MJ, et al. Potent, selective, and orally bioavailable matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis. Bioorg Med Chem 2005; 13: 6629–44

    PubMed  Article  CAS  Google Scholar 

  33. Wada CK. The evolution of the matrix metalloproteinase inhibitor drug discovery program at Abbott laboratories. Curr Top Med Chem 2004; 4: 1255–67

    PubMed  Article  CAS  Google Scholar 

  34. Naglich JG, Jure-Kunkel M, Gupta E, et al. Inhibition of angiogenesis and metastasis in two murine models by the matrix metalloproteinase inhibitor, BMS-275291. Cancer Res 2001; 61: 8480–5

    PubMed  CAS  Google Scholar 

  35. Gatto C, Rieppi M, Borsotti P, et al. BAY 12-9566, a novel inhibitor of matrix metalloproteinases with antiangiogenic activity. Clin Cancer Res 1999; 5: 3603–7

    PubMed  CAS  Google Scholar 

  36. Lee M, Bernardo MM, Meroueh SO, et al. Synthesis of chiral 2-(4-phenoxy phenylsulfonylmethyl) thiiranes as selective gelatinase inhibitors. Org Lett 2005; 7: 4463–5

    PubMed  Article  CAS  Google Scholar 

  37. Grams F, Brandstetter H, D’Alo S, et al. Pyrimidine-2,4,6-triones: a new effective and selective class of matrix metalloproteinase inhibitors. Biol Chem 2001; 382: 1277–85

    PubMed  Article  CAS  Google Scholar 

  38. Dive V, Georgiadis D, Matziari M, et al. Phosphinic peptides as zinc metalloproteinase inhibitors. Cell Mol Life Sci 2004; 61: 2010–9

    PubMed  Article  CAS  Google Scholar 

  39. Pochetti G, Gavuzzo E, Campestre C, et al. Structural insight into the stereoselective inhibition of MMP-8 by enantiomeric sulfonamide phosphonates. J Med Chem 2006; 49: 923–31

    PubMed  Article  CAS  Google Scholar 

  40. Salo T, Soini Y, Oiva J, et al. 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 2006 Aug 28; 111(3): 358–64

    PubMed  Article  Google Scholar 

  41. Breuer E, Frant J, Reich R. Recent non-hydroxamate matrix metalloproteinase inhibitors. Expert Opin Ther Patents 2005; 15: 253–69

    Article  CAS  Google Scholar 

  42. Dublanchet AC, Ducrot P, Andrianjara C, et al. Structure-based design and synthesis of novel non-zinc chelating MMP-12 inhibitors. Bioorg Med Chem Lett 2005 Aug 15; 15(16): 3787–90

    PubMed  Article  CAS  Google Scholar 

  43. Lombard C, Saulnier J, Wallach J. Assays of matrix metalloproteinases (MMPs) activities: a review. Biochimie 2005; 87: 265–72

    PubMed  Article  CAS  Google Scholar 

  44. Cheng XC, Fang H, Xu WF. Advances in assays of matrix metalloproteinases (MMPs) and their inhibitors. J Enzyme Inhib Med Chem 2008; 23(2): 154–67

    PubMed  Article  CAS  Google Scholar 

  45. Lauer-Fields JL, Minond D, Chase PS, et al. High throughput screening of potentially selective MMP-13 exosite inhibitors utilizing a triple-helical FRET substrate. Bioorg Med Chem 2009; 17: 990–1005

    PubMed  Article  CAS  Google Scholar 

  46. Hajduk PJ, Greer J. A decade of fragment-based drug design: strategic advances and lessons learned. Nat Rev Drug Discov 2007; 6: 211–9

    PubMed  Article  CAS  Google Scholar 

  47. Saghatelian A, Jessani N, Joseph A, et al. Activity-based probes for the proteomic profiling of metalloproteases. Proc Natl Acad Sci U S A 2004; 101: 10000–5

    PubMed  Article  CAS  Google Scholar 

  48. Chan EWS, Chattopadhaya S, Panicker RC, et al. Developing photoactive affinity probes for proteomic profiling: hydroxamate-based probes for metalloproteases. J Am Chem Soc 2004; 126: 14435–46

    PubMed  Article  CAS  Google Scholar 

  49. Fingleton B. Matrix metalloproteinases as valid clinical targets. Curr Pharm Des 2007; 13(3): 333–46

    PubMed  Article  CAS  Google Scholar 

  50. Fingleton B. MMPs as therapeutic targets: still a viable option? Semin Cell Dev Biol 2008 Feb; 19(1): 61–8

    PubMed  Article  CAS  Google Scholar 

  51. Turk B. Targeting proteases: successes, failures and future prospects. Nat Rev Drug Discov 2006 Sep; 5(9): 785–99

    PubMed  Article  CAS  Google Scholar 

  52. Abbenante G, Fairlie DP. Protease inhibitors in the clinic. Med Chem 2005; 1:71–104

    PubMed  Article  CAS  Google Scholar 

  53. Fingleton B. MMP inhibitor clinical trials: the past, present, and future. In: Edwards D, Høyer-Hansen G, Blasi F, et al., editors. The cancer degradome: proteases and cancer biology. New York: Springer Science+Business Media, 2008: 759–85

    Chapter  Google Scholar 

  54. Krzeski P, Buckland-Wright C, Balint G, et al. Development of musculoskeletal toxicity without clear benefit after administration of PG-116800, a matrix metalloproteinase inhibitor, to patients with knee osteoarthritis: a randomized, 12-month, double-blind, placebo-controlled study. Arthritis Res Ther 2007; 9: R109

    PubMed  Article  Google Scholar 

  55. Steward WP, Thomas AL. Marimastat: the clinical development of a matrix metalloproteinase inhibitor. Expert Opin Investig Drugs 2000; 9: 2913–22

    PubMed  Article  CAS  Google Scholar 

  56. Pharmaceutical R&D pipeline news. Pharmaprojects, 2009 database. London: Informa UK Ltd, 2009

    Google Scholar 

  57. Thabet MM, Huizinga TW. Drug evaluation: apratastat, a novel TACE/MMP inhibitor for rheumatoid arthritis. Curr Opin Investig Drugs 2006 Nov; 7(11): 1014–9

    PubMed  CAS  Google Scholar 

  58. Scrip Daily Online 2000 Mar 30; S00659818 [PharmaProjects database]

  59. Eatock M, Cassidy J, Johnson J, et al. A dose-finding and pharmacokinetic study of the matrix metalloproteinase inhibitor MMI270 (previously termed CGS27023A) with 5-FU and folinic acid. Cancer Chemother Pharmacol 2005 Jan; 55(1): 39–46

    PubMed  Article  CAS  Google Scholar 

  60. Saloni S, Chan D. Licensing highlights. IDrugs 2005; 8:172–7

    Google Scholar 

  61. Wielockx B, Libert C, Wilson C. Matrilysin (matrix metalloproteinase-7): a new promising drug target in cancer and inflammation? Cytokine Growth Factor Rev 2004; 15:111–5

    PubMed  Article  CAS  Google Scholar 

  62. Hudson MP, Armstrong PW, Ruzyllo W, et al. Effects of selective matrix metalloproteinase inhibitor (PG-116800) to prevent ventricular remodeling after myocardial infarction: results of the PREMIER (Prevention of Myocardial Infarction Early Remodeling) trial. J Am Coll Cardiol 2006; 48: 15–20

    PubMed  Article  CAS  Google Scholar 

  63. van Beusekom HM, Post MJ, Whelan DM, et al. Metalloproteinase inhibition by batimastat does not reduce neointimal thickening in stented atherosclerotic porcine femoral arteries. Cardiovasc Radiat Med 2003; 4: 186–91

    PubMed  Article  Google Scholar 

  64. Araujo CM, Rando GA, Mauro MF, et al. Batimastateluting stent implantation for the treatment of coronary artery disease: results of the Brazilian pilot study. Arq Bras Cardiol 2005; 84: 256–60

    PubMed  Google Scholar 

  65. Ferdinandy P. Peroxynitrite: just an oxidative/nitrosative stressor or a physiological regulator as well? Br J Pharmacol 2006; 148: 1–3

    PubMed  Article  CAS  Google Scholar 

  66. Ferdinandy P, Schulz R. Nitric oxide, superoxide, and peroxynitrite in myocardial ischaemia-reperfusion injury and preconditioning. Br J Pharmacol 2003; 138: 532–43

    PubMed  Article  CAS  Google Scholar 

  67. Schulz R. Intracellular targets of matrix metalloproteinase-2 in cardiac disease: rationale and therapeutic approaches. Annu Rev Pharmacol Toxicol 2007; 47: 211–42

    PubMed  Article  CAS  Google Scholar 

  68. Csonka C, Csont T, Onody A, et al. Preconditioning decreases ischemia/reperfusion-induced peroxynitrite formation. Biochem Biophys Res Commun 2001; 285: 1217–9

    PubMed  Article  CAS  Google Scholar 

  69. Lalu M, Csonka C, Giricz Z, et al. Preconditioning decreases ischemia/reperfusion-induced release and activation of matrix metalloproteinase-2. Biochem Biophys Res Commun 2002; 296: 937–41

    PubMed  Article  CAS  Google Scholar 

  70. Cheung PY, Sawicki G, Wozniak M, et al. Matrix metalloproteinase-2 contributes to ischemia-reperfusion injury in the heart. Circulation 2000; 101: 1833–9

    PubMed  Article  CAS  Google Scholar 

  71. Giricz Z, Lalu MM, Csonka C, et al. Hyperlipidemia attenuates the infarct size-limiting effect of ischemic preconditioning: role of matrix metalloproteinase-2 inhibition. J Pharmacol Exp Ther 2006; 316: 154–61

    PubMed  Article  CAS  Google Scholar 

  72. Gao CQ, Sawicki G, Suarez-Pinzon WL, et al. Matrix metalloproteinase-2 mediates cytokine-induced myocardial contractile dysfunction. Cardiovasc Res 2003; 57: 426–33

    PubMed  Article  CAS  Google Scholar 

  73. Sariahmetoglu M, Crawford BD, Leon H, et al. Regulation of matrix metalloproteinase-2 (MMP-2) activity by phosphorylation. FASEB J 2007; 21: 2486–95

    PubMed  Article  CAS  Google Scholar 

  74. Ferdinandy P, Schulz R, Baxter GF. Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning. Pharmacol Rev 2007; 59: 418–58

    PubMed  Article  CAS  Google Scholar 

  75. Kandasamy AD, Schulz R. Glycogen synthase kinase-3b is activated by matrix metalloproteinase-2 mediated proteolysis in cardiomyoblasts. Cardiovasc Res 2009 Sep 1; 83(4): 698–706

    PubMed  Article  CAS  Google Scholar 

  76. Bereczki E, Gonda S, Csont T, et al. Overexpression of biglycan in the heart of transgenic mice: an antibody microarray study. J Proteome Res 2007; 6: 854–61

    PubMed  Article  CAS  Google Scholar 

  77. Downey JM, Cohen MV. Why do we still not have cardioprotective drugs? Circ J 2009; 73(7): 1171–7

    PubMed  Article  Google Scholar 

  78. Overall CM, Kleifeld O. Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer 2006; 6: 227–39

    PubMed  Article  CAS  Google Scholar 

  79. Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 2002; 295: 2387–92

    PubMed  Article  CAS  Google Scholar 

  80. Curino AC, Engelholm LH, Yamada SS, et al. Intracellular collagen degradation mediated by uPARAP/Endo180 is a major pathway of extracellular matrix turnover during malignancy. J Cell Biol 2005; 169: 977–85

    PubMed  Article  CAS  Google Scholar 

  81. Wagenaar-Miller RA, Engelholm LH, Gavard J, et al. Complementary roles of intracellular and pericellular collagen degradation pathways in vivo. Mol Cell Biol 2007; 27: 6309–22

    PubMed  Article  CAS  Google Scholar 

  82. Yang E, Boire A, Agarwal A, et al. Blockade of PAR1 signaling with cell-penetrating pepducins inhibits Akt survival pathways in breast cancer cells and suppresses tumor survival and metastasis. Cancer Res 2009; 69: 6223–31

    PubMed  Article  CAS  Google Scholar 

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Acknowledgements

The authors acknowledge support from the National Research and Technology Office by grants TAMOP-422-08/1-2008-0013 as well as NKFP-A1-2006-0029 to develop MMPIs (for further details see http://www.mmpharma.com) and partial support from the European Commission (FP-6: LSHC-CT-2006-037559).

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Correspondence to György Dormán.

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Dormán, G., Cseh, S., Hajdú, I. et al. Matrix Metalloproteinase Inhibitors. Drugs 70, 949–964 (2010). https://doi.org/10.2165/11318390-000000000-00000

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Keywords

  • Surface Plasmon Resonance
  • Periodontal Disease
  • Batimastat
  • Catalytic Zinc
  • Backbone Fragment