Challenges in Matrix Metalloproteinases Inhibition
Abstract
:1. Introduction
2. Specific Endogenous Inhibitor-Tissue Inhibitors of Metalloproteinases (TIMPs)
3. Non-Specific Endogenous Inhibitors
4. Synthetic Inhibitors
- -
- A functional group able to chelate the zinc ion (II)-zinc binding group (ZBG). The first generation inhibitors used hydroxamate (CONHO−) but the second generation use carboxylate (COO−), thiolates (S−), phosphonyls (PO2−), for example (Figure 3);
- -
- At least one functional group that promotes hydrogen bonding with the protein backbone;
- -
- One or more side chains undergoing Van der Waals interactions with enzyme subsites.
4.1. Hydroxamate-Based Inhibitors
- (i)
- The stoichiometric orientation of the substituent at R1 position is crucial for the activity;
- (ii)
- The phenylpropyl group was established as the best substituent at position R1;
- (iii)
- Hydrophobic substituents at R2’ position and N-metiamides at R3’ position were considered as the most appropriate.
4.1.1. Succinyl Hydroxamic Acid-Based Inhibitors
- -
- The variation of the acyl group and the second amino acid (AA) leads to the activity against different MMPs.
- -
- The R group interacts with the S1’ pocket.
4.1.2. Sulfonamide Hydroxamic Acid-Based Inhibitors
4.1.3. Phosphamides Hydroxamic Acid-Based Inhibitors
4.2. Non-Hydroxamate-Based Inhibitors
4.2.1. Thiolates-Based Inhibitors
4.2.2. Carboxylates-Based Inhibitors
4.2.3. Phosphorus-Based Inhibitors
4.2.4. Nitrogen-Based Inhibitors
4.2.5. Heterocyclic Bidentate-Based Inhibitors
4.2.6. Tetracyclines-Based Inhibitors
4.2.7. Mechanism-Based Inhibitors
4.3. Catalytic Domain (Non-Zinc Binding) Inhibitors
4.4. Allosteric and Exosite Inhibitors
4.5. Antibody-Based Inhibitors
5. Why Do MMP is Fail?
- -
- The observed effects can be a consequence of the manipulated absence of MMP, being a compensation mechanism;
- -
- The mouse models are unable to replicate the complexity of any human disease. The mouse models serve to recreate specific processes or sets of processes but not the physiological changes that occur in humans.
6. Conclusions
- -
- Inhibition of other metalloenzymes;
- -
- Lack of specificity within the MMP family;
- -
- Poor pharmacokinetics;
- -
- Dose-limiting side effects/toxicity;
- -
- In vivo instability;
- -
- Low oral availability/inability to assess inhibition efficacy.
Funding
Conflicts of Interest
References
- Cui, N.; Hu, M.; Khalil, R.A. Biochemical and Biological Attributes of Matrix Metalloproteinases. Prog. Mol. Biol. Transl. Sci. 2017, 147, 1–73. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, J.; Khalil, R.A. Matrix Metalloproteinase Inhibitors as Investigational and Therapeutic Tools in Unrestrained Tissue Remodeling and Pathological Disorders. Prog. Mol. Biol. Transl. Sci. 2017, 148, 355–420. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Klein, T.; Bischoff, R. Physiology and pathophysiology of matrix metalloproteases. Amino Acids 2011, 41, 271–290. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Maskos, K. Crystal structures of MMPs in complex with physiological and pharmacological inhibitors. Biochimie 2005, 87, 249–263. [Google Scholar] [CrossRef]
- Cerofolini, L.; Fragai, M.; Luchinat, C. Mechanism and Inhibition of Matrix Metalloproteinases. Curr. Med. Chem. 2019, 26, 2609–2633. [Google Scholar] [CrossRef]
- Fischer, T.; Senn, N.; Riedl, R. Design and Structural Evolution of Matrix Metalloproteinase Inhibitors. Chemistry 2019, 25, 7960–7980. [Google Scholar] [CrossRef]
- Nagase, H.; Visse, R.; Murphy, G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc. Res. 2006, 69, 562–573. [Google Scholar] [CrossRef] [Green Version]
- Amălinei, C.; Căruntu, I.D.; Bălan, R.A. Biology of metalloproteinases. Rom. J. Morphol. Embryol. 2007, 48, 323–334. [Google Scholar]
- Visse, R.; Nagase, H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: Structure, function, and biochemistry. Circ. Res. 2003, 92, 827–839. [Google Scholar] [CrossRef] [Green Version]
- Tallant, C.; Marrero, A.; Gomis-Rüth, F.X. Matrix metalloproteinases: Fold and function of their catalytic domains. Biochim. Biophys. Acta. 2010, 1803, 20–28. [Google Scholar] [CrossRef]
- Verma, R.P.; Hansch, C. Matrix metalloproteinases (MMPs): Chemical-biological functions and (Q)SARs. Bioorg. Med. Chem. 2007, 15, 2223–2268. [Google Scholar] [CrossRef] [PubMed]
- Murphy, G.; Nagase, H. Progress in matrix metalloproteinase research. Mol. Asp. Med. 2008, 29, 290–308. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mannello, F.; Medda, V. Nuclear localization of matrix metalloproteinases. Prog. Histochem. Cytochem. 2012, 47, 27–58. [Google Scholar] [CrossRef] [PubMed]
- Rangasamy, L.; Geronimo, B.D.; Ortín, I.; Coderch, C.; Zapico, J.M.; Ramos, A.; de Pascual-Teresa, B. Molecular Imaging Probes Based on Matrix Metalloproteinase Inhibitors (MMPIs). Molecules 2019, 24, 2982. [Google Scholar] [CrossRef] [Green Version]
- Vandenbroucke, R.E.; Dejonckheere, E.; Libert, C. A therapeutic role for matrix metalloproteinase inhibitors in lung diseases? Eur. Respir. J. 2011, 38, 1200–1214. [Google Scholar] [CrossRef] [PubMed]
- Nuti, E.; Tuccinardi, T.; Rossello, A. Matrix metalloproteinase inhibitors: New challenges in the era of post broad-spectrum inhibitors. Curr. Pharm. Des. 2007, 13, 2087–2100. [Google Scholar] [CrossRef]
- Georgiadis, D.; Yiotakis, A. Specific targeting of metzincin family members with small-molecules inhibitors: Progress toward a multifarious challenge. Bioorg. Med. Chem. 2008, 8781–8794. [Google Scholar] [CrossRef]
- Jacobsen, J.A.; Major Jourden, J.L.; Miller, M.T.; Cohen, S.M. To bind zinc or not to bind zinc: An examination of innovative approaches to improved metalloproteinase inhibition. Biochim. Biophys. Acta 2010, 1803, 72–94. [Google Scholar] [CrossRef] [Green Version]
- Whittaker, M.; Floyd, C.D.; Brown, P.; Gearing, A.J. Design and therapeutic application of matrix metalloproteinase inhibitors. Chem. Rev. 1999, 99, 2735–2776. [Google Scholar] [CrossRef]
- Tokuhara, C.K.; Santesso, M.R.; Oliveira, G.S.N.; Ventura, T.M.D.S.; Doyama, J.T.; Zambuzzi, W.F.; Oliveira, R.C. Updating the role of matrix metalloproteinases in mineralized tissue and related diseases. J. Appl. Oral Sci. 2019, 27, e20180596. [Google Scholar] [CrossRef]
- Liu, Y.; Tjäderhane, L.; Bresch, L.; Mazzoni, A.; Li, N.; Mao, J.; Pashley, D.H.; Tay, F.R. Limitations in Bonding to Dentin and Experimental Strategies to Prevent Bond Degradation. J. Dent. Res. 2011, 90, 953–968. [Google Scholar] [CrossRef] [PubMed]
- Young, D.; Das, N.; Anowai, A.; Dufour, A. Matrix Metalloproteases as Influencers of the Cells’ Social Media. Int. J. Mol. Sci. 2019, 20, 3847. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kwan, J.A.; Schulze, C.J.; Wang, W.; Leon, H.; Sariahmetoglu, M.; Sung, M.; Sawicka, J.; Sims, D.E.; Sawicki, G.; Schulz, R. Matrix metalloproteinase-2 (MMP-2) is present in the nucleus of cardiac myocytes and is capable of cleaving poly (ADP-ribose) polymerase (PARP) in vitro. Faseb J. 2004, 18, 690–692. [Google Scholar] [CrossRef]
- Cauwe, B.; Van den Steen, P.E.; Opdenakker, G. The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix metalloproteinases. Crit. Rev. Biochem. Mol. Biol. 2007, 42, 113–185. [Google Scholar] [CrossRef] [Green Version]
- Cauwe, B.; Opdenakker, G. Intracellular substrate cleavage: A novel dimension in the biochemistry, biology and pathology of matrix metalloproteinases. Crit Rev. Biochem. Mol. Biol. 2010, 45, 351–423. [Google Scholar] [CrossRef]
- Jobin, P.G.; Butler, G.S.; Overall, C.M. New intracellular activities of matrix metalloproteinases shine in the moonlight. Biochim Biophys Acta Mol. Cell Res. 2017, 1864, 2043–2055. [Google Scholar] [CrossRef]
- Fields, G.B. The Rebirth of Matrix Metalloproteinase Inhibitors: Moving Beyond the Dogma. Cells 2019, 8, 984. [Google Scholar] [CrossRef] [Green Version]
- Li, K.; Tay, F.R.; Yiu, C.K.Y. The past, present and future perspectives of matrix metalloproteinase inhibitors. Pharmacol. Ther. 2020, 207, 107465. [Google Scholar] [CrossRef]
- Hu, J.; Van den Steen, P.E.; Sang, Q.X.; Opdenakker, G. Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat. Rev. Drug Discov. 2007, 6, 480–498. [Google Scholar] [CrossRef] [PubMed]
- Murphy, G. Tissue inhibitors of metalloproteinases. Genome Biol. 2011, 12, 233. [Google Scholar] [CrossRef]
- Folgueras, A.R.; Pendás, A.M.; Sánchez, L.M.; López-Otín, C. Matrix metalloproteinases in cancer: From new functions to improved inhibition strategies. Int. J. Dev. Biol 2004, 48, 411–424. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Maskos, K.; Bode, W. Structural basis of matrix metalloproteinases and tissue inhibitors of metalloproteinases. Mol. Biotechnol. 2003, 25, 241–266. [Google Scholar] [CrossRef]
- Arbeláez, L.F.; Bergmann, U.; Tuuttila, A.; Shanbhag, V.P.; Stigbrand, T. Interaction of matrix metalloproteinases-2 and -9 with pregnancy zone protein and alpha2-macroglobulin. Arch. Biochem. Biophys. 1997, 347, 62–68. [Google Scholar] [CrossRef] [PubMed]
- Serifova, X.; Ugarte-Berzal, E.; Opdenakker, G.; Vandooren, J. Homotrimeric MMP-9 is an active hitchhiker on alpha-2-macroglobulin partially escaping protease inhibition and internalization through LRP-1. Cell Mol. Life Sci. 2019. [Google Scholar] [CrossRef]
- 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 2005, 87, 393–402. [Google Scholar] [CrossRef]
- Castelhano, A.L.; Billedeau, R.; Dewdney, N.; Donnelly, S.; Horne, S.; Kurz, L.J.; Liak, T.J.; Martin, R.; Uppington, R.; Yuan, Z.; et al. Novel indolactam-based inhibitors of matrix metalloproteinases. Bioorg. Med. Chem. Lett. 1995, 5, 1415–1420. [Google Scholar] [CrossRef]
- Gimeno, A.; Beltrán-Debón, R.; Mulero, M.; Pujadas, G.; Garcia-Vallvé, S. Understanding the variability of the S1’ pocket to improve matrix metalloproteinase inhibitor selectivity profiles. Drug Discov. Today 2019, 1, 38–57. [Google Scholar] [CrossRef]
- Moore, W.M.; Spilburg, C.A. Peptide hydroxamic acids inhibit skin collagenase. Biochem. Biophys. Res. Commun. 1986, 136, 390–395. [Google Scholar] [CrossRef]
- Moore, W.M.; Spilburg, C.A. Purification of human collagenases with a hydroxamic acid affinity column. Biochemistry 1986, 25, 5189–5195. [Google Scholar] [CrossRef]
- Reich, R.; Thompson, E.W.; Iwamoto, Y.; Martin, G.R.; Deason, J.R.; Fuller, G.C.; Miskin, R. Effects of inhibitors of plasminogen activator, serine proteinases, and collagenase IV on the invasion of basement membranes by metastatic cells. Cancer Res. 1988, 48, 3307–3312. [Google Scholar]
- Xue, C.B.; He, X.; Roderick, J.; DeGrado, W.F.; Cherney, R.J.; Hardman, K.D.; Nelson, D.J.; Copeland, R.A.; Jaffee, B.D.; Decicco, C.P. Design and synthesis of cyclic inhibitors of matrix metalloproteinases and TNF-alpha production. J. Med. Chem. 1998, 41, 1745–1748. [Google Scholar] [CrossRef] [PubMed]
- Steinman, D.H.; Curtin, M.L.; Garland, R.B.; Davidsen, S.K.; Heyman, H.R.; Holms, J.H.; Albert, D.H.; Magoc, T.J.; Nagy, I.B.; Marcotte, P.A.; et al. The design, synthesis, and structure-activity relationships of a series of macrocyclic MMP inhibitors. Bioorg. Med. Chem. Lett. 1998, 8, 2087–2092. [Google Scholar] [CrossRef]
- Martin, S.F.; Oalmann, C.J.; Liras, S. Cyclopropanes as conformationally restricted peptide isosteres. Design and synthesis of novel collagenase inhibitors. Tetrahedron 1993, 49, 3521–3532. [Google Scholar] [CrossRef]
- Tamaki, K.; Tanzawa, K.; Kurihara, S.; Oikawa, T.; Monma, S.; Shimada, K.; Sugimura, Y. Synthesis and structure-activity relationships of gelatinase inhibitors derived from matlystatins. Chem. Pharm. Bull. (Tokyo) 1995, 43, 1883–1893. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Conradi, R.A.; Hilgers, A.R.; Ho, N.F.; Burton, P.S. The influence of peptide structure on transport across Caco-2 cells. Pharm Res. 1991, 8, 1453–1460. [Google Scholar] [CrossRef] [PubMed]
- Babine, R.E.; Bender, S.L. Molecular Recognition of Proteinminus signLigand Complexes: Applications to Drug Design. Chem. Rev. 1997, 97, 1359–1472. [Google Scholar] [CrossRef]
- Hirayama, R.; Yamamoto, M.; Tsukida, T.; Matsuo, K.; Obata, Y.; Sakamoto, F.; Ikeda, S. Synthesis and biological evaluation of orally active matrix metalloproteinase inhibitors. Bioorg. Med. Chem. 1997, 5, 765–778. [Google Scholar] [CrossRef]
- Graf von Roedern, E.; Grams, F.; Brandstetter, H.; Moroder, L. Design and synthesis of malonic acid-based inhibitors of human neutrophil collagenase (MMP8). J. Med. Chem. 1998, 41, 339–345. [Google Scholar] [CrossRef]
- Albini, A.; D’Agostini, F.; Giunciuglio, D.; Paglieri, I.; Balansky, R.; De Flora, S. Inhibition of invasion, gelatinase activity, tumor take and metastasis of malignant cells by N-acetylcysteine. Int. J. Cancer 1995, 61, 121–129. [Google Scholar] [CrossRef]
- Müller, J.C.; von Roedern, E.G.; Grams, F.; Nagase, H.; Moroder, L. Non-peptidic cysteine derivatives as inhibitors of matrix metalloproteinases. Biol Chem 1997, 378, 1475–1480. [Google Scholar] [CrossRef]
- Foley, M.A.; Hassman, A.S.; Drewry, D.H.; Greer, D.G.; Wagner, C.D.; Feldman, P.L.; Berman, J.; Bickett, D.M.; McGeehan, G.M.; Lambert, M.H.; et al. Rapid synthesis of novel dipeptide inhibitors of human collagenase and gelatinase using solid phase chemistry. Bioorg. Med. Chem. Lett. 1996, 6, 223–243. [Google Scholar] [CrossRef]
- Johnson, W.H.; Roberts, N.A.; Borkakoti, N. Collagenase inhibitors: Their design and potential therapeutic use. J. Enzym. Inhib. 1987, 2, 1–22. [Google Scholar] [CrossRef] [PubMed]
- Valérie, M.; Mirand, C.; Decarme, M.; Emonard, H.; Hornebeck, W. MMPs inhibitors: New succinylhydroxamates with selective inhibition of MMP-2 over MMP-3. Bioorg. Med. Chem. Lett. 2003, 13, 2843–2846. [Google Scholar] [CrossRef]
- Pikul, S.; McDow Dunham, K.L.; Almstead, N.G.; De, B.; Natchus, M.G.; Anastasio, M.V.; McPhail, S.J.; Snider, C.E.; Taiwo, Y.O.; Chen, L.; et al. Design and synthesis of phosphinamide-based hydroxamic acids as inhibitors of matrix metalloproteinases. J. Med. Chem. 1999, 42, 87–94. [Google Scholar] [CrossRef] [PubMed]
- Aureli, L.; Gioia, M.; Cerbara, I.; Monaco, S.; Fasciglione, G.F.; Marini, S.; Ascenzi, P.; Topai, A.; Coletta, M. Structural bases for substrate and inhibitor recognition by matrix metalloproteinases. Curr. Med. Chem. 2008, 15, 2192–2222. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- MacPherson, L.J.; Bayburt, E.K.; Capparelli, M.P.; Carroll, B.J.; Goldstein, R.; Justice, M.R.; Zhu, L.; Hu, S.; Melton, R.; Fryer, L.; et al. Discovery of CGS 27023A, a Non-Peptidic, Potent, and Orally Active Stromelysin Inhibitor That Blocks Cartilage Degradation in Rabbits. J. Med. Chem. 1997, 40, 2525–2532. [Google Scholar] [CrossRef] [PubMed]
- Barta, T.E.; Becker, D.P.; Bedell, L.J.; De Crescenzo, G.A.; McDonald, J.J.; Munie, G.E.; Rao, S.; Shieh, H.S.; Stegeman, R.; Stevens, A.M.; et al. Synthesis and activity of selective MMP inhibitors with an aryl backbone. Bioorg. Med. Chem. Lett. 2000, 10, 2815–2817. [Google Scholar] [CrossRef]
- Noe, M.C.; Natarajan, V.; Snow, S.L.; Mitchell, P.G.; Lopresti-Morrow, L.; Reeves, L.M.; Yocum, S.A.; Carty, T.J.; Barberia, J.A.; Sweeney, F.J.; et al. Discovery of 3,3-dimethyl-5-hydroxypipecolic hydroxamate-based inhibitors of aggrecanase and MMP-13. Bioorg. Med. Chem. Lett. 2005, 15, 2808–2811. [Google Scholar] [CrossRef]
- Hu, J.; Fiten, P.; Van den Steen, P.E.; Chaltin, P.; Opdenakker, G. Simulation of evolution-selected propeptide by high-throughput selection of a peptidomimetic inhibitor on a capillary DNA sequencer platform. Anal. Chem. 2005, 77, 2116–2124. [Google Scholar] [CrossRef]
- Hu, J.; Dubois, V.; Chaltin, P.; Fiten, P.; Dillen, C.; Van den Steen, P.E.; Opdenakker, G. Inhibition of lethal endotoxin shock with an L-pyridylalanine containing metalloproteinase inhibitor selected by high-throughput screening of a new peptide library. Comb. Chem. High. Throughput Screen 2006, 9, 599–611. [Google Scholar] [CrossRef]
- Bhowmick, M.; Tokmina-Roszyk, D.; Onwuha-Ekpete, L.; Harmon, K.; Robichaud, T.; Fuerst, R.; Stawikowska, R.; Steffensen, B.; Roush, W.; Wong, H.R.; et al. Second Generation Triple-Helical Peptide Inhibitors of Matrix Metalloproteinases. J. Med. Chem. 2017, 60, 3814–3827. [Google Scholar] [CrossRef] [PubMed]
- Beszant, B.; Bird, J.; Gaster, L.M.; Harper, G.P.; Hughes, I.; Karran, E.H.; Markwell, R.E.; Miles-Williams, A.J.; Smith, S.A. Synthesis of novel modified dipeptide inhibitors of human collagenase: Beta-mercapto carboxylic acid derivatives. J. Med. Chem. 1993, 36, 4030–4039. [Google Scholar] [CrossRef] [PubMed]
- Baxter, A.D.; Bird, J.; Bhogal, R.; Massil, T.; Minton, K.J.; Montana, J.; Owen, D.A. A novel series of matrix metalloproteinase inhibitors for the treatment of inflammatory disorders. Bioorg. Med. Chem. Lett. 1997, 7, 897–902. [Google Scholar] [CrossRef]
- Campbell, D.A.; Xiao, X.Y.; Harris, D.; Ida, S.; Mortezaei, R.; Ngu, K.; Shi, L.; Tien, D.; Wang, Y.; Navre, M.; et al. Malonyl alpha-mercaptoketones and alpha-mercaptoalcohols, a new class of matrix metalloproteinase inhibitors. Bioorg. Med. Chem. Lett. 1998, 8, 1157–1162. [Google Scholar] [CrossRef]
- Hurst, D.R.; Schwartz, M.A.; Jin, Y.; Ghaffari, M.A.; Kozarekar, P.; Cao, J.; Sang, Q.X. Inhibition of enzyme activity of and cell-mediated substrate cleavage by membrane type 1 matrix metalloproteinase by newly developed mercaptosulphide inhibitors. Biochem. J. 2005, 392, 527–536. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fray, M.J.; Dickinson, R.P.; Huggins, J.P.; Occleston, N.L. A potent, selective inhibitor of matrix metalloproteinase-3 for the topical treatment of chronic dermal ulcers. J. Med. Chem. 2003, 46, 3514–3525. [Google Scholar] [CrossRef]
- Chapman, K.T.; Kopka, I.E.; Durette, P.L.; Esser, C.K.; Lanza, T.J.; Izquierdo-Martin, M.; Niedzwiecki, L.; Chang, B.; Harrison, R.K.; Kuo, D.W. Inhibition of matrix metalloproteinases by N-carboxyalkyl peptides. J. Med. Chem. 1993, 36, 4293–4301. [Google Scholar] [CrossRef]
- Reiter, L.A.; Rizzi, J.P.; Pandit, J.; Lasut, M.J.; McGahee, S.M.; Parikh, V.D.; Blake, J.F.; Danley, D.E.; Laird, E.R.; Lopez-Anaya, A.; et al. Inhibition of MMP-1 and MMP-13 with phosphinic acids that exploit binding in the S2 pocket. Bioorg. Med. Chem. Lett. 1999, 9, 127–132. [Google Scholar] [CrossRef]
- 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. 2004, 47, 325–336. [Google Scholar] [CrossRef]
- Pochetti, G.; Gavuzzo, E.; Campestre, C.; Agamennone, M.; Tortorella, P.; Consalvi, V.; Gallina, C.; Hiller, O.; Tschesche, H.; Tucker, P.A.; et al. Structural insight into the stereoselective inhibition of MMP-8 by enantiomeric sulfonamide phosphonates. J. Med. Chem. 2006, 49, 923–931. [Google Scholar] [CrossRef]
- Vandooren, J.; Knoops, S.; Aldinucci Buzzo, J.L.; Boon, L.; Martens, E.; Opdenakker, G.; Kolaczkowska, E. Differential inhibition of activity, activation and gene expression of MMP-9 in THP-1 cells by azithromycin and minocycline versus bortezomib: A comparative study. PLoS ONE 2017, 12, e0174853. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ikejiri, M.; Bernardo, M.M.; Bonfil, R.D.; Toth, M.; Chang, M.; Fridman, R.; Mobashery, S. Potent mechanism-based inhibitors for matrix metalloproteinases. J. Biol. Chem. 2005, 280, 33992–34002. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bernardo, M.M.; Brown, S.; Li, Z.H.; Fridman, R.; Mobashery, S. Design, synthesis, and characterization of potent, slow-binding inhibitors that are selective for gelatinases. J. Biol. Chem. 2002, 277, 11201–11207. [Google Scholar] [CrossRef] [Green Version]
- Fingleton, B. MMPs as therapeutic targets--still a viable option? Semin. Cell Dev. Biol. 2008, 19, 61–68. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Class | MMP | |
---|---|---|
Collagenases | MMP-1, Collagenase-1, Interstitial or Fibroblast collagenases | |
MMP-8, Collagenase-2, or Neutrophil collagenases | ||
MMP-13 or Collagenase 3 | ||
Gelatinases | MMP-2 or Gelatinase A | |
MMP-9 or Gelatinase B | ||
Stromelysin | MMP-3 or Stromelysin-1 | |
MMP-10 or Stromelysin-2 | ||
MMP-11 | ||
Matrilysin | MMP-7 | |
MMP-26, Matrilysin-2, or Endometase | ||
Membrane-type | Type I transmembrane protein | MMP-14 or MT1-MMP |
MMP-15 or MT2-MMP | ||
MMP-16 or MT3-MMP | ||
MMP-24 or MT5-MMP | ||
Glycosylphosphatidylinositol (GPI)-anchored | MMP17 or MT4-MMP | |
MMP-25 or MT6-MMP | ||
Other MMPs | MMP-12 | |
MMP-19 | ||
MMP-20 | ||
MMP-21 | ||
MMP-23 | ||
MMP-27 | ||
MMP-28 |
Specific Inhibitor | Tissue Inhibitor of Metalloproteinases (TIMP) | |
---|---|---|
Endogenous inhibitor | Non-specifics inhibitors | α2-macroglobulin |
Tissue factor pathway inhibitor (TFPI) | ||
Membrane-bound β-amyloid precursor protein | ||
C-terminal proteinases enhancer protein | ||
Reversion-inducing cystein-rich protein with Kasal domain motifs (RECK) | ||
GPI-anchored glycoprotein | ||
Synthetic inhibitor | Hydroxamate-based inhibitors | |
Non-hydroxamate-based inhibitors | ||
Catalytic domain (non-zinc binding) inhibitors | ||
Allosteric and exosite inhibitors | ||
Antibody-based inhibitors |
TIMP | Expression | Inhibition | Inhibition Mode |
---|---|---|---|
1 | Several tissues with transcription inducible by cytokines and hormones | Strong interaction with MMP-1, -2, -3, and -9 Weak interaction with MT1-MMP, MT3-MMP, MT5-MMP, and MMP-19 | TIMP-1 forms a complex with pro-MMP-9 by binding to the hemopexin domain |
2 | Constitutive expression | Strong interaction with MMP-2 | TIMP-2 has four residues in the N-terminal domain and an adjacent CD-loop region, which allows interaction between TIMP and the active center of MMP-2 |
3 | In response to mitogenic stimulation and during cell cycle progression | MMP-1, -2, -3, -9, and -13 | The inhibition mode is different from the other TIMPs for its unusual localization, as it is largely sequestered into the extracellular matrix or at the cell surface via heparan sulphate proteoglycans |
4 | Especially abundant in the heart, but is also expressed in injured tissue | MMP-2 and -14 | - |
Non-Specific Inhibitor | Inhibition |
---|---|
α2-macroglobulin | MMP-2 and -9 |
Tissue factor pathway inhibitor | MMP-1 and -2 |
Membrane-bound β-amyloid precursor protein | MMP-2 |
C-terminal proteinase enhancer protein | MMP-2 |
Reversion-inducing-cysteine-rich protein with Kasal motifs (RECK) | MMP-2, -9, and -14 |
GPI-anchored glycoprotein | - |
Name | Molecule | α Substituent | Effect |
---|---|---|---|
Batimastat | Thienylthiomethylene | Not available orally | |
Marimastat | Hydroxyl group (directed to the protein surface, allowing the formation of hydrogen bonds with solvent) | Available orally |
Marimastat (BB-2516) IC50: MMP-1 = 5 nM; MMP-2 = 6 nM; MMP-3 = 200 nM; MMP-7 = 20 nM; MMP-8 = 2 nM; MMP-9 = 3 nM; MMP-12 < 5 nM; MMP-13 = 0.74 nM; MMP-14 = 1.8 nM | Analogue of Marimastat IC50: MMP-1 = 3 nM; MMP-2 = 1.1 nM; MMP-3 = 14 nM; MMP-7 = 0.8 nM; MMP-8 = 0.5 nM; MMP-9 = 0.9 nM; MMP-10 = 0.45 nM; MMP-14 = 94 nM; MMP-15 = 20 nM; MMP-16 = 35 nM | SE205 Ki: MMP-1 = 1.2 nM; MMP-3 = 32.7 nM; MMP-9 = 1.8 nM | ||
IC50: MMP-1 = 131 nM; MMP-2 = 9.5 nM; MMP-3 = 8.9 nM; MMP-7 = 3.3 nM | SC903 Ki: MMP-1 = 2.8 nM; MMP-3 = 24.1 nM; MMP-9 = 2.6 nM | IC50: MMP-1 = 4 nM; MMP-2 = 3 nM; MMP-3 = 30 nM; MMP-7 = 20 nM; MMP-8 = 20 nM; MMP-9 = 9 nM | ||
SC-44463 IC50: MMP-1 = 20 nM; MMP-2 = 6 nM; MMP-3 = 30 nM; MMP-7 = 30 nM | BB-16 IC50: MMP-1 = 5 nM; MMP-2 = 10 nM; MMP-3 = 40 nM; MMP-7 = 60 nM; MMP-8 = 7 nM | Ro-31-9790 IC50: MMP-1 = 10 nM; MMP-2 = 8 nM; MMP-3 = 700 nM; MMP-14 = 1.9 nM | ||
Ro-32-0554 IC50: MMP-1 = 0.5 nM; MMP-3 = 9.1 nM; MMP-9 = 4.3 nM | IC50: MMP-1 = 10 nM; MMP-2 = 400 nM; MMP-3 = 4.5 μM | Ro-32-3555 Ki: MMP-1 = 3 nM; MMP-2 = 154 nM; MMP-3 = 527 nM; MMP-8 = 4 nM; MMP-9 = 59 nM; MMP-13 = 3 nM | ||
IC50: MMP-1 = 40 nM | IC50: MMP-1 = 29 μM | IC50: MMP-1 = 10 μM | ||
IC50: MMP-1 = 9 nM | Analogue of Marimastat IC50: MMP-1 = 1 μM; MMP-2 = 15 nM; MMP-3 = 500 nM; MMP-7 = 10 μM; MMP-8 = 30 nM; MMP-9 = 15 nM | Ki: MMP-1 = 2 nM; MMP-3 = 3 nM; MMP-9 < 1 nM | ||
Ki: MMP-1 = 1.3 nM; MMP-2 = 1.1 nM; MMP-3 = 187 nM | Ki: MMP-1 = 6.5 nM; MMP-2 = 20 nM; MMP-3 = 240 nM | IC50: MMP-1 = 6 nM; MMP-2 = 30 nM; MMP-3 = 40 nM | ||
IC50: MMP-1 = 375 nM; MMP-2 < 0.15 nM; MMP-3 = 18 nM; MMP-9 = 1.5 nM | IC50: MMP-1 = 20 nM; MMP-2 = 2 nM; MMP-3 = 100 nM; MMP-9 = 2 μM | IC50: MMP-2 = 20 nM; MMP-3 = 300 nM; MMP-9 = 1 nM | ||
KB-R7785 IC50: MMP-1 = 3 nM; MMP-2 = 7.5 nM; MMP-3 = 1.9 nM; MMP-9 = 3.9 nM | IC50: MMP-1 = 5.4 nM; MMP-2 = 8.4 nM; MMP-3 = 2.3 nM; MMP-9 = 5 nM; MMP-14 = 2.3 nM | IC50: MMP-1 = 5 nM; MMP-2 = 1 nM; MMP-3 = 15 nM; MMP-9 = 1 nM | ||
IC50: MMP-1 = 150 nM | IC50: MMP-3 = 300 nM | Matlystatin B IC50: MMP-2 = 1.7 μM; MMP-9 = 570 nM | ||
R-94138 IC50: MMP-2 = 38 nM; MMP-3 = 28 nM; MMP-7 = 23 nM; MMP-9 = 1.2 nM; MMP-13 = 38 nM | Ki: MMP-1 > 8.3 μM; MMP-2 = 3.4 μM; MMP-3 = 1.3 μM; MMP-7 > 8.3 μM; MMP-14 = 7.7 μM | Ki: MMP-1 > 12.5 μM; MMP-2 = 1.1 μM; MMP-3 = 100 nM; MMP-7 = 200 nM; MMP-14 = 1.8 nM | ||
Ki: MMP-1 = 200 nM | IC50: MMP-1 > 5 μM; MMP-2 = 35 nM; MMP-3 = 3.56 nM; MMP-7 > 5 μM; MMP-9 = 304 nM; MMP-12 = 17 nM; MMP-14 = 772 nM; MMP-15 = 60 nM | Ki: MMP-1 = 33.16 μM; MMP-2 = 6.3 μM; MMP-8 = 171 nM; MMP-9 = 4.468 μM | ||
Ki: MMP-1 = 5.248 μM; MMP-2 > 3 μM; MMP-3 > 4.5 μM; MMP-9 < 1 nM; MMP-13 > 5 μM | BB-1101 IC50: MMP-1 = 10 nM; MMP-2 = 5 nM; MMP-3 = 30 nM; MMP-7 = 30 nM; MMP-8 = 3 nM; MMP-9 = 3 nM | IC50: MMP-1 = 3.1 nM; MMP-2 = 4.2 nM; MMP-3 = 25 nM | ||
IC50: MMP-1 = 1.1 nM; MMP-2 = 1.1 nM; MMP-3 = 2.3 nM; MMP-7 = 2.2 nM | OPB-3206 IC50: MMP-1 = 700 nM; MMP-2 = 5 μM; MMP-3 = 2 μM; MMP-9 = 500 nM | IC50: MMP-8 = 300 nM | ||
Batimastat (BB-94) IC50: MMP-1 = 3 nM; MMP-2 = 4 nM; MMP-3 = 20 nM; MMP-7 = 6 nM; MMP-8 = 10 nM; MMP-9 = 1 nM; MMP-13 = 1 nM; MMP-14 = 2.8 nM Ki: MMP-1 = 10 nM; MMP-2 = 4 nM; MMP-3 = 20 nM; MMP-8 = 10 nM; MMP-9 = 1 nM | Ilomastat (GM6001; Galardin®) IC50: MMP-1 = 0.4 nM; MMP-2 = 0.4 nM; MMP-3 = 0.19 nM; MMP-14 = 5.2 nM Ki: MMP-1 = 0.4 nM; MMP-2 = 0.39 nM; MMP-3 = 26 nM; MMP-8 = 0.18 nM; MMP-9 = 0.2 nM | Analogue of Ilomastat IC50: MMP-2 = 1.3 nM; MMP-3 = 179 nM | ||
IC50: MMP-1 = 3 nM; MMP-3 = 280 nM; MMP-7 = 18 nM | Ki: MMP-1 = 3 nM | IC50: MMP-1 = 8 μM; MMP-2 = 8 μM; MMP-3 = 3.5 μM | ||
IC50: MMP-1 = 3.3 μM; MMP-2 = 32 nM; MMP-3 = 57 nM | IC50: MMP-3 = 3.4 μM | IC50: MMP-3 = 15 nM | ||
IC50: MMP-1 > 50 μM; MMP-2 > 120 μM; MMP-3 = 80 μM; MMP-8 > 120 μM | IC50: MMP-2 = 52 μM; MMP-3 = 200 μM; MMP-8 = 1200 μM | IC50: MMP-8 = 121 μM | ||
PKF 242-484 Ki: MMP-1 = 3.6 nM; MMP-2 = 0.1 nM; MMP-3 = 0.9 nM; MMP-9 = 1 nM; MMP-13 = 4.5 nM | CT1746 Ki: MMP-1 = 122 nM; MMP-2 = 0.04 nM; MMP-3 = 10.9 nM; MMP-7 = 136 nM; MMP-9 = 0.17 nM | ONO-4817 IC50: MMP-1 = 1600 nM; MMP-9 = 2.1 nM Ki: MMP-2 = 0.73 nM; MMP-3 = 42 nM; MMP-7 = 2500 nM; MMP-12 = 0.45 nM; MMP-13 = 1.1 nM | ||
AS 111793# IC50: MMP-1 = 20 nM | MMPI-I IC50: MMP-1 = 1 μM; MMP-3 = 150 μM; MMP-8 = 1 μM; MMP-9 = 30 μM | |||
IC50: MMP-1 = 0.1 nM; MMP-3 = 9 nM; MMP-8 = 0.4 nM; MMP-9 = 0.2 nM | IC50: MMP-1 = 30 nM; MMP-2 = 20 nM; MMP-3 = 500 nM; MMP-7 = 200 nM; MMP-8 = 20 nM | Ki: MMP-1 = 1450 nM; MMP-3 = 15 nM; MMP-8 = 2 nM; MMP-9 = 3 nM | ||
Ki: MMP-1 = 8 nM; MMP-3 = 28 nM; MMP-8 < 2 nM; MMP-9 = 1 nM | IC50: MMP-1 = 100 nM; MMP-2 = 0.07 nM; MMP-3 = 3 nM; MMP-7 = 700 nM; MMP-8 = 4 nM; MMP-9 = 1 nM | |||
IC50: MMP-1 = 11 nM; MMP-3 = 1.04 μM | IC50: MMP-1 = 600 nM; MMP-2 = 3 μM; MMP-3 = 50 nM; MMP-7 = 4 nM | Ki: MMP-1 = 7.56 μM; MMP-7 = 622 nM; MMP-13 = 7.3 nM | ||
IC50: MMP-1 = 6 μM; MMP-2 = 200 nM; MMP-3 = 100 nM | IC50: MMP-2 = 5 nM | Ki: MMP-2 = 2.2 nM | ||
IC50: MMP-7 = 1 510 μM; MMP-12 = 149 μM | Ki: MMP-1 > 4.949 μM; MMP-2 > 3.333 μM; MMP-9 > 2.128 μM | Ki: MMP-2 > 15 μM; MMP-8 > 15 μM; MMP-9 > 15 μM; MMP-12 = 410 nM; MMP-13 > 15 μM; MMP-14 = 3.07 μM | ||
IC50: MMP-1 = 5.9 μM; MMP-2 = 750 nM; MMP-3=2.1 nM; MMP-9 = 560 nM; MMP-14 = 930 nM | IC50: MMP-1 = 51 μM; MMP-2 = 1.79 μM; MMP-3 = 5.9 nM; MMP-9 = 840 nM; MMP-13 = 73 nM; MMP-14 = 1.9 μM | Ki: MMP-1 > 4.946 μM; MMP-2 > 3.333 μM; MMP-3 > 4.501 μM; MMP-7 > 6.368 μM; MMP-8 > 3.058 μM; MMP-9 > 2.128 μM; MMP-10 > 5.346 μM; MMP-12 > 6.023 μM; MMP-13 > 5.025 μM; MMP-14 > 5.290 μM; MMP-15 > 7.088 μM | ||
IC50: MMP-1 = 4.6 μM; MMP-2 = 4 nM; MMP-3 = 42 nM; MMP-7 > 10 μM; MMP-9 = 120 nM | Ki: MMP-1 > 4.494 μM; MMP-2 > 3.333 μM; MMP-3 = 82 nM; MMP-7 = 25 nM; MMP- 8 > 3.1 μM; MMP-9 > 2.128 μM; MMP-13 > 5.025 μM; MMP-14 > 5.290 μM; MMP-15 > 7.088 μM; MMP-16 > 5.554 μM | Ki: MMP-1 > 5 μM; MMP-2 > 3 μM; MMP-3 = 762 nM; MMP-8 = 2.05 μM; MMP-9 > 3 μM; MMP-10 > 1.650 μM; MMP-13 > 5 μM; MMP-14 = 163 nM; MMP-15 = 1.7 μM | ||
Ki: MMP-1 > 2 μM; MMP-2 > 2 μM; MMP-3 > 2 μM; MMP-7 = 834 nM; MMP-8 = 126 nM; MMP-9 > 2 μM; MMP-10 > 2 μM; MMP-12 > 2 μM; MMP-13 = 653 nM; MMP-14 > 2 μM; MMP-15 > 2 μM; MMP-16 > 2 μM | Ki: MMP-1 = 30 μM; MMP-2 = 2.05 μM; MMP-3 = 141 nM; MMP-7 = 259 nM; MMP-8 = 257 nM; MMP-9 = 10.34 μM; MMP-13 = 1.417 μM; MMP-14 = 15.872 μM; MMP-15 = 3.997 μM; MMP-16 = 1.599 μM |
CGS-27023A (MMI270) IC50: MMP-1 = 33 nM; MMP-2 = 11 nM; MMP-3 = 13 nM; MMP-9 = 8 nM; MMP-12 = 7.7 nM; MMP-13 = 6 nM Ki: MMP-1 = 3 nM; MMP-2 = 20 nM; MMP-3 = 148 nM; MMP-8 = 1.9 nM | Analogue of CGS-27023A IC50: MMP-1 = 104 nM; MMP-2 = 0.7 nM; MMP-3 = 0.7 nM; MMP-9 = 2.5 nM; MMP-13 = 12 nM | Ki: MMP-1 = 770 nM; MMP-2 = 620 nM; MMP-3 = 4.1 μM; MMP-9 = 620 nM | |||
CGS-25966 Ki: MMP-3 = 92 nM | NNGH IC50: MMP-12 = 72 nM Ki: MMP-10 = 0.6 nM | IC50: MMP-1 = 2 nM; MMP-2 = 20 nM; MMP-3 = 30 nM; MMP-7 = 20 nM; MMP-9 = 7 nM | IC50: MMP-1 = 6 nM; MMP-2 = 900 nM; MMP-3 = 200 M; MMP-7 = 200 nM; MMP-8 = 200 nM; MMP-9 = 2μM; MMP-13 = 400 nM | ||
Prinomastat (AG3340) Ki: MMP-1 = 8.3 nM; MMP-2 = 0.05 nM; MMP-3 = 0.3 nM; MMP-7 = 54 nM; MMP-9 = 0.26 nM; MMP-13 = 0.03 nM; MMP-14 = 0.33 nM | CP-471,474 IC50: MMP-1 = 1170 nM; MMP-2 = 0.7 nM; MMP-3 = 16 nM; MMP-9 = 13 nM | IC50: MMP-1 > 10 μM; MMP-2 = 3.3 nM; MMP-13 = 12 nM | |||
IC50: MMP-1 = 196 nM; MMP-2 = 0.01 nM; MMP-9 = 1 nM | RS-113,456 IC50: MMP-3 = 5.2 nM Ki: MMP-1 = 70 nM; MMP-2 = 0.054 nM; MMP-7 = 240 nM; MMP-8 = 0.13 nM; MMP-9 = 0.065 nM; MMP-12 = 0.15 nM; MMP-13 = 0.17 nM; MMP-14 = 0.089 nM | RS-130,830 Ki: MMP-1 = 590 nM; MMP-2 = 0.22 nM; MMP-3 = 9.3 nM; MMP-7 = 1.2 μM; MMP-9 = 0.58 nM; MMP-13 = 0.52 nM | |||
RS-104,966 Ki: MMP-1 = 23 nM; MMP-13 = 0.13 nM | IC50: MMP-1 = 3 245 nM; MMP-9 = 7 nM; MMP-13 = 4 nM | IC50: MMP-2 = 960 nM; MMP-13 = 1.17 μM; MMP-14 = 3.41 μM | |||
IC50: MMP-1 = 310 nM | IC50: MMP-1 = 920 nM; MMP-13 = 0.95 nM | IC50: MMP-1 = 841 nM; MMP-9 = 33 nM; MMP-13 = 29 nM | IC50: MMP-1 = 763 nM; MMP-9 = 2 nM; MMP-13 = 2 nM | ||
MMP-8 inhibitor I IC50: MMP-8 = 4 nM | Ro-32-7315 IC50: MMP-1 = 500 nM; MMP-2 = 250 nM; MMP-3 = 210 nM; MMP-7 = 310 nM; MMP-9 = 100 nM; MMP-12 = 11 nM; MMP-13 = 110 nM | IC50: MMP-1 = 346 μM; MMP-9 = 24 μM | |||
PGE-4410186 IC50: MMP-1 = 24 nM; MMP-3 = 18.4 nM; MMP-7 = 30 nM; MMP-9 = 2.7 nM | MMP-9 inhibitor I IC50: MMP-1 = 1.05 nM; MMP-9 = 5 nM; MMP-13 = 113 nM | Ki: MMP-1 = 1.085 μM; MMP-2 = 1 nM; MMP-9 = 10 nM; MMP-13 = 3 nM | |||
MMPI-II (MMP-2/MMP-9 inhibitor II) IC50: MMP-1 = 970 nM; MMP-2 = 17 nM; MMP-3 > 1000 nM; MMP-7 = 800 nM; MMP-9 = 30 nM; MMP-14 = 17 nM | IC50: MMP-1> 50 μM; MMP-2 = 12 nM; MMP-3 = 4.5 μM; MMP-7 > 50 μM; MMP-9 = 200 nM | IC50: MMP-1 = 147 nM; MMP-2 = 0.09 nM; MMP-3 = 50 nM; MMP-7 > 1 μM; MMP-8 = 1.6 nM; MMP-9 = 6.7 nM; MMP-14 = 9.8 nM | |||
Ki: MMP-1 = 2 μM; MMP-2 = 10 nM; MMP-3 = 500 nM | IC50: MMP-1 = 200 nM; MMP-9 = 0.43 nM | IC50: MMP-1 = 2.471 μM; MMP-7 = 961 nM; MMP-8 = 35 nM; MMP-9 = 777 nM; MMP-13 = 96 nM; MMP-14 = 582 nM | |||
IC50: MMP-1 = 37.3 μM; MMP-2 = 664 nM; MMP-9 = 5.5 μM; MMP-13 = 2.277 μM; MMP-14 = 24 μM | IC50: MMP-1 = 8.78 μM; MMP-2 = 355 nM; MMP-9 = 1.67 μM; MMP-13 = 230 nM; MMP-14 = 4.71 μM | Ki: (S enantiomer) MMP-3 = 19 nM (R enantiomer) MMP-3 = 36 nM | |||
IC50: MMP-1 = 2.268 μM; MMP-9 = 152 nM; MMP-13 = 18 nM | IC50: MMP-1 = 14 μM; MMP-2 = 529 nM; MMP-3 = 1 nM; MMP-9 = 2.42 μM; MMP-14 = 20.1 μM |
IC50 (X = H; Y = (CH2)2C6H5; Z = Me; R = Ph): MMP-1 = 252 nM; MMP-3 = 700 nM IC50 (X = H; Y = (CH2)2C6H5; Z = Ph; R = Ph): MMP-1 = 854 nM; MMP-3 = 1.75 μM IC50 (X = Me; Y = CH2C6H5; Z = Me; R = Ph): MMP-1 = 120 nM; MMP-3 = 67.9 nM IC50 (X = Me; Y = CH2C6H5; Z = Et; R = Ph): MMP-1 = 608 nM; MMP-3 = 700 nM IC50 (X = Me; Y = CH2C6H5; Z = Ph; R = Ph): MMP-1 = 6.79 μM; MMP-3 = 10.3 μM IC50 (X = CH2i-Pr; Y = CH2C6H5; Z = Me; R = Ph): MMP-1 = 20.5 nM; MMP-3 = 24.4 nM IC50 (X = CH2i-Pr; Y = CH2C6H5; Z = Me; R = Me): MMP-1 = 518 nM; MMP-3 = 1.04 μM | |
IC50 (X = CH2i-Pr; Y = H; Z = CH3): R isómer, MMP-1 = 2.51 μM; MMP-3 = 2.55 μM S isomer: MMP-1 > 100 μM; MMP-3 = 130.5 μM IC50 (X = CH2i-Pr; Y = CH2C6H5; Z = CH3): R isomer, MMP-1 = 20.5 nM; MMP-3 = 24.4 nM S isomer, MMP-1 = 7.12 μM; MMP-3 = 9.17 μM IC50 (X = CH3; Y = CH2C6H5; Z = C2H5): R isomer, MMP-1 = 608 nM; MMP-3 = 700 nM S isomer, MMP-1 = 33.3 μM; MMP-3 = 49.3 μM | |
IC50 (X = H; Y = (CH2)2C6H5): MMP-1 = 525 nM; MMP-3 = 700 nM IC50 (X = CH3; Y = CH2C6H5): MMP-1 = 120 nM; MMP-3 = 67.9 nM IC50 (X = CH3; Y = n-C6H13): MMP-1 = 1.29 μM; MMP-3 = 1.6 μM IC50 (X = CH2i-Pr; Y = H): MMP-1 = 2.51 μM; MMP-3 = 2.55 μM IC50 (X = CH2i-Pr; Y = CH2C6H5): MMP-1 = 20.5 nM; MMP-2 = 13.3 nM; MMP-3 = 24.4 nM; MMP-7 = 886 nM; MMP-8 = 5.3 nM; MMP-9 = 20.6 nM; MMP-13 = 7.4 nM |
IC50 (R = H): MMP-1 = 360 nM IC50 (R = Me): MMP-1 = 220 nM | IC50: MMP-1 = 2.5 nM | IC50: MMP-3 = 260 nM; MMP-8 = 50 nM; MMP-9 = 90 nM | D2163 IC50: MMP-1 = 25 nM; MMP-2 = 41 nM; MMP-3 = 157 nM; MMP-8 = 10 nM; MMP-9 = 25 nM; MMP-13 = 4 nM | ||
Rebimastat (BMS-275231) IC50: MMP-1 = 25 nM; MMP-2 = 41 nM; MMP-3 = 157 nM; MMP-9 = 25 nM; MMP-13 = 4 nM | Ki (n = 0): MMP-2 = 1.2 nM; MMP-3 = 39 nM; MMP-12 = 18 nM Ki (n = 1): MMP-3 = 210 nM | ||||
IC50: MMP-3 = 45 nM; MMP-8 = 3 nM; MMP-9 = 5 nM | Ki: MMP-1 = 49 nM; MMP-2 = 1.1 nM; MMP-3 = 470 nM; MMP-7 = 40 nM; MMP-9 = 0.57 nM; MMP-14 = 24 nM | Ki: MMP-8 = 1.2 μM | |||
IC50 (X = CH): MMP-1 = 30 nM IC50 (X = N): MMP-1 > 100 μM | IC50: MMP-3 = 2.5 μM | IC50: MMP-3 = 600 nM | |||
IC50: MMP-1 = 890 nM; MMP-3 = 4.6 μM; MMP-9 = 4.5 μM | IC50: MMP-1 = 15 nM; MMP-3 = 16 nM; MMP-9 = 0.3 nM | IC50: MMP-1 > 10 μM; MMP-3 = 36 nM; MMP-9 = 20 nM | |||
IC50 (X, Y = O): MMP-1 = 10 nM; MMP-2 = 8 nM; MMP-9 = 0.1 nM IC50 (X = OH; Y = H): MMP-1 = 140 nM; MMP-3 = 430 nM; MMP-9 = 12 nM IC50 (X = H; Y = O): MMP-1 = 5 nM; MMP-3 = 9 nM; MMP-9 = 0.14 nM | IC50: MMP-1 = 823 nM; MMP-3 = 207 nM; MMP-9 = 26 nM | IC50: MMP-1 = 70 nM; MMP-13 = 0.1 nM | |||
IC50: MMP-1 = 1.5 μM; MMP-3 = 500 nM; MMP-8 = 4 nM; MMP-13 = 0.5 nM | Ki: MMP-2 = 46 nM; MMP-3 = 10 μM; MMP-9 = 100 nM; MMP-14 = 210 nM | Ki: MMP-2 = 1.3 μM; MMP-7 > 2.5 μM; MMP-8 = 2.7 μM; MMP-9 = 6.3 μM; MMP-13 = 1.7 μM | |||
PNU-141803 Ki: MMP-2 = 49.5 μM; MMP-3 = 310 nM | PNU-142372 Ki: MMP-2 = 3 μM; MMP-3 = 18 nM | IC50: MMP-1 = 65 nM; MMP-3 > 20 μM; MMP-9 = 2.9 μM | |||
IC50: MMP-1 = 15 μM | CP-271485 IC50: MMP-9 = 5.1 μM; MMP-12 > 100 μM | SB-3CT Ki: MMP-1 = 206 μM; MMP-2 = 14 nM; MMP-3 = 15 μM; MMP-7 = 96 μM; MMP-9 = 600 nM | |||
Ki: MMP-1 = 11 μM; MMP-2 = 50 nM; MMP-14 = 590 nM | Ki: MMP-2 = 16 nM; MMP-3 = 3.6 μM; MMP-7 = 295 μM; MMP-9 = 180 nM; MMP-14 = 900 nM | Ki: MMP-1 = 5.4 μM; MMP-2 = 110 nM; MMP-3 = 12.2 μM; MMP-7 = 39 μM; MMP-9 = 130 nM; MMP-14 = 680 nM |
L-758,354 Ki: MMP-2 = 17 nM; MMP-3 = 10 nM | Ki: MMP-3 = 42 nM | Ki: MMP-3 = 21 nM | |||
Tanomastat (BAY 12-9566) Ki: MMP-1 > 5 μM; MMP-2 = 11 nM; MMP-3 = 134 nM; MMP-9 = 301 nM; MMP-13 = 1.47 μM | Ki: MMP-1 = 0.9 nM; MMP-3 = 15 nM; MMP-9 = 3 nM | AG 3067 Ki: MMP-1 > 1000 nM; MMP-2 = 16 nM; MMP-3 = 2 nM; MMP-7 = 614 nM | |||
IC50: MMP-2 = 34.2 μM; MMP-3 = 23 nM; MMP-9 = 30.4 μM; MMP-13 = 2.3 μM; MMP-14 = 66.9 μM | AG 3365 Ki: MMP-2 = 0.04 nM; MMP-3 = 1.5 nM; MMP-7 = 305 nM; MMP-13 = 0.05 nM | AG 3433 Ki: MMP-2 = 0.9 nM; MMP-3 = 19 nM; MMP-7 = 4545 μM; MMP-13 = 3.3 nM | |||
An-1 IC50: MMP-2 = 9.3 nM; MMP-9 = 201 nM | IC50: MMP-1 > 98 μM; MMP-2 = 4.52 μM; MMP-3 > 98 μM; MMP-7 > 98 μM; MMP-12 = 520 nM; MMP-13 = 12 μM; MMP-14 = 43.5 μM | IC50: MMP-1 > 98 μM; MMP-12 = 62 nM; MMP-13 = 970 nM | |||
IC50: MMP-1 = 3.2 μM; MMP-2 = 5 nM; MMP-3 = 12 nM; MMP-9 = 8.3 μM | IC50: MMP-1 > 98 μM; MMP-12 = 1.150 μM; MMP-13 = 26.1 μM | PD-0359601 IC50: MMP-2 = 6.6 μM; MMP-3 = 3.2 nM; MMP-8 = 160 nM; MMP-12 = 1.7 nM | |||
IC50: MMP-9 = 91 nM Ki: MMP-1 = 20 nM; MMP-3 = 91 nM; MMP-9 = 91 nM | IC50 (X = NH): MMP-1 = 90 nM IC50 (X = CH2): MMP-1 = 380 nM | ||||
IC50: MMP-1 > 400 μM; MMP-2 = 132 nM; MMP-3 = 81 nM; MMP-7 = 1.1 μM; MMP-8 = 42 nM; MMP-9 > 7 μM; MMP-13 = 1.8 nM; MMP-14 = 5 μM | IC50: MMP-13 = 6.72 nM | ||||
PF-00356231 IC50: MMP-2 > 100 μM; MMP-3 = 390 nM; MMP-8 = 1.7 μM; MMP-9 = 980 nM; MMP-12 = 14 nM; MMP-13 = 270 nM | MMP 408 IC50: MMP-1 > 6 μM; MMP-3 = 351 nM; MMP-7 > 6 μM; MMP-9 = 1.3 μM; MMP-12 = 2 nM; MMP-13 = 120 nM; MMP-14 = 1.1 μM | IC50: MMP-3 = 50 nM | |||
Ki: MMP-1 > 10 μM; MMP-2 > 1.06 μM; MMP-3 = 3.88 μM; MMP-7 = 2.01 μM; MMP-8 = 410 nM; MMP-9 > 10 μM; MMP-12 = 1 nM; MMP-13 = 684 nM; MMP-14 = 3.01 μM | Ki: MMP-1 = 127 nM; MMP-3 = 5.819 μM; MMP- = 671 nM; MMP-9 = 2.232 μM; MMP-12 = 2.5 nM; MMP-13 = 501 nM; MMP-14 = 968 nM | ||||
Ki (X = H; Y = Me): MMP-1 = 760 nM; MMP-2 = 200 nM; MMP-3 = 470 nM Ki (X = C4H9; Y = Me): MMP-1 = 5.9 μM; MMP-2 = 3.5 nM; MMP-3 = 18 nM Ki (X = H; Y = Phthbutyl): MMP-1 = 720 nM; MMP-2 = 86 nM; MM-3 = 8 nM | Ki (Y = [H2]-Phthbutyl): MMP-1 > 10 μM; MMP-2 = 6 nM; MMP-3 = 0.36 nM Ki (Y = Me): MMP-1 > 10 μM; MMP-2 = 310 nM; MMP-3 = 68 nM | Ki: MMP-1 > 25 μM; MMP-2 > 25 μM; MMP-3 > 25 μM; MMP-7 > 25 μM; MMP-8 > 25 μM; MMP-9 > 25 μM; MMP-12 > 25 μM; MMP-13 = 4.4 nM; MMP-14 > 25 μM; MMP-15 > 25 μM; MMP-16 > 25 μM; MMP-24 > 25 μM; MMP-25 > 25 μM; MMP-26 > 25 μM | |||
IC50: MMP-1 > 1000 nM; MMP-2 = 19 nM; MMP-3 > 1000 nM; MMP-7 > 1000 nM; MMP-9 = 32 nM | Ki: MMP-8 = 205 nM; MMP-12 = 3.3 nM; MMP-13 = 18 nM; MMP-14 = 1.054 μM | ||||
Ki: MMP-2 = 57 nM; MMP-3 = 2.164 μM; MMP-8 = 5.3 nM; MMP-13 = 338 nM | Ki: MMP-1 = 2.5 μM; MMP-2 = 8.1 μM; MMP-3 = 13.5 μM; MMP-8 = 17 nM; MMP-9 = 6.6 μM | Ki: MMP-1 = 67 μM; MMP-2 = 192 nM; MMP-3 = 40 nM; MMP-7 = 626 nM; MMP-8 = 271 nM; MMP-9 = 1.265 μM; MMP-11 = 18.4 μM; MMP-12 = 0.19 nM; MMP-13 = 49 nM; MMP-14 = 140 nM |
Ki: MMP-2 = 30 μM; MMP-8 = 38.9 μM; MMP-9 = 35.6 μM; MMP-11 = 230nM; MMP-13 = 15.7 μM; MMP-14 = 160 μM | Ki: MMP-2 = 4.65 μM; MMP-8 = 18.4 μM; MMP-9 = 3.91 μM; MMP-11 = 0.11 μM; MMP-13 = 4.7 μM; MMP-14 = 30.1 μM | Cyclohexylamine salt of (S/R)-1-(3′-methylbiphenyl-4-sulfonylamino)-methylpropyl phosphonic acid IC50 (S isomer): MMP-3 > 100 μM IC50 (R isomer): MMP-1 = 150 nM; MMP-2 = 1.5 nM; MMP-3 = 52 nM; MMP-7 = 460 nM; MMP-8 = 1.4 nM; MMP-9 = 8 nM; MMP-13 = 2.6 nM; MMP-14 = 79 nM Ki (S isomer): MMP-2 = 1.2 μM; MMP-8 = 0.7 μM Ki (R isomer): MMP-2 = 5 nM; MMP-3 = 0.04 μM; MMP-8 = 0.6 nM |
IC50: MMP-1 = 160 nM; MMP-2 = 20 nM; MMP-3 = 150 nM; MMP-7 = 1.4 μM; MMP-8 = 1.1 nM; MMP-9 = 59 nM; MMP-13 = 13 nM; MMP-14 = 32 nM | IC50: MMP-1 > 100 μM; MMP-2 = 0.02 μM; MMP-3 = 90 μM; MMP-8 = 20 μM; MMP-9 > 100 μM | IC50: MMP-1 > 100 μM; MMP-2 = 4 μM; MMP-3 > 100 μM; MMP-8 > 100 μM; MMP-9 = 20 μM; MMP-12 > 100 μM; MMP-13 > 100 μM |
IC50 (X = CH2; Y = Ph(CH2)2; Z = iC4H9; R = Ph): MMP-1 > 10 μM; MMP-2 = 20 nM; MMP-3 = 1.4 nM Ki (X = NH; Y = iC4H9; Z = 2-naphthyl; R = Me): MMP-3 = 7 nM | Ki: MMP-1 = 3 μM; MMP-3 = 6 nM | IC50: MMP-1 = 270 nM |
IC50 (R = PhO(CH2)3): MMP-1 > 30 μM; MMP-13 = 30 nM IC50 (R-PhCH2): MMP-1 = 690 nM; MMP-3 = 1.2 μM; MMP-13 = 14 nM | IC50: MMP-1 > 5 μM; MMP-2 = 1.5 nM; MMP-7 > 2.5 μM; MMP-9 = 13 nM; MMP-13 = 1.6 nM | IC50: MMP-1 = 20 nM |
IC50: MMP-1 > 100 μM; MMP-2 > 100 μM; MMP-9 > 100 μM | IC50: MMP-1 = 180 nM |
Ro-206-0222 IC50: MMP-1 = 4.310 μM; MMP-9 = 2 nM | Ro-28-2653 IC50: MMP-1 = 16 μM; MMP-2 = 12 nM; MMP-3 = 1.8 μM; MMP-8 = 15 nM; MMP-9 = 16 nM; MMP-14 = 10 nM | IC50: MMP-1 = 2.4 μM; MMP-2 = 397 nM; MMP-3 = 17 μM; MMP-8 = 394 nM; MMP-9 = 540 nM; MMP-12 = 619 nM; MMP-13 = 0.36 nM; MMP-14 = 540 nM | |||
IC50: MMP-13 = 0.87 nM; MMP-14 = 23 nM | IC50: MMP-13 = 1 nM; MMP-14 = 220 nM | IC50: MMP-8 = 107 nM; MMP-9 = 20 nM | |||
Ki: MMP-1 > 5 μM; MMP-2 = 1.8 nM; MMP-9 = 1.9 nM; MMP-13 = 0.33 nM | IC50: MMP-2 = 0.14 μM; MMP-8 = 0.14 μM; MMP-12 = 0.22 μM; MMP-13 = 0.36 nM | ||||
Ki: MMP-2 = 2.17 μM; MMP-3 > 4.50 μM; MMP-7 > 6.37 μM; MMP-12 = 1.02 μM | GW-3333 IC50: MMP-1 = 19 μM; MMP-3 = 20 nM; MMP-9 = 16 nM | S-3304 IC50: MMP-2 = 2 nM; MMP-9 = 10 nM | |||
AZD-126 IC50: MMP-9 = 4.5 nM; MMP-12 = 6.1 nM | IC50: MMP-1 > 50 μM; MMP-2 = 610 nM; MMP-3 = 10 nM | IC50: MMP-1 > 50 μM; MMP-2 > 50 μM; MMP-3 = 19 nM | |||
IC50: MMP-1 > 50 μM; MMP-2 = 4.4 μM; MMP-3 = 77 nM; MMP-7 > 50 μM; MMP-8 = 245 nM; MMP-9 = 32.3 μM; MMP-12 = 85 nM; MMP-13 = 6.6 μM | IC50: MMP-1 > 50 μM; MMP-2 = 9.3 μM; MMP-3 = 0.24 μM; MMP-7 > 50 μM; MMP-8 = 64 nM; MMP-9 > 50 μM; MMP-12 = 22 nM; MMP-13 = 20.6 μM | IC50: MMP-1 > 50 μM; MMP-2 = 16.5 μM; MMP-3 = 41.7 μM; MMP-7 > 50 μM; MMP-8 = 3.8 μM; MMP-9 > 50 μM; MMP-12 = 1.2 μM; MMP-13 = 16.5 μM | |||
IC50: MMP-1 > 50 μM; MMP-2 = 7.6 μM; MMP-3> 50 μM; MMP-7 > 50 μM; MMP-8 = 5.0 μM; MMP-9 > 50 μM; MMP-12 = 6.7 μM; MMP-13 = 6.7 μM | IC50: MMP-1 > 50 μM; MMP-2 = 0.92 μM; MMP-3 = 0.56 μM; MMP-7 > 50 μM; MMP-8 = 86 nM; MMP-9 = 27.1 μM; MMP-12 = 18 nM; MMP-13 = 4.1 μM | IC50: MMP-1 > 400 μM; MMP-2 = 135 nM; MMP-3 = 81 nM; MMP-7 = 1.1 μM; MMP-8 = 42 nM; MMP-9 > 7 μM; MMP-13 = 1.8 nM; MMP-14 = 5 μM | |||
IC50: MMP-1 = 14 μM; MMP-2 = 529 nM; MMP-3 = 1 nM; MMP-9 = 2.42 μM; MMP-14 = 20.1 μM | KI: MMP-1 > 500 μM; MMP-9 = 6 μM | IC50: MMP-1 > 1 μM; MMP-2 = 5 nM; MMP-3 = 56 nM; MMP-9 = 2.4 nM; MMP-12 = 2.5 nM | |||
IC50: MMP-1 = 30 nM; MMP-2 = 9.8 nM; MMP-3 = 1.7 μM; MMP-7 = 475 nM; MMP-9 = 3 nM; MMP-14 = 17 μM | IC50: MMP-1 > 100 μM; MMP-2 > 100 μM; MMP-3 > 100 μM; MMP-7 > 100 μM; MMP-8 > 100 μM; MMP-9 > 100 μM; MMP-12 > 100 μM; MMP-13 > 100 μM; MMP-14 > 100 μM | IC50: MMP-1 > 10 μM; MMP-7 > 10 μM; MMP-9 > 10 μM; MMP-13 = 12 nM; MMP-14 > 10 μM | |||
IC50: MMP-1 > 30 μM; MMP-2 > 30 μM; MMP-3 > 30 μM; MMP-7 > 30 μM; MMP-8 > 100 μM; MMP-9 > 100 μM; MMP-12 > 100 μM; MMP-13 = 0.67 nM; MMP-14 > 30 μM; MMP-17 > 30 μM | IC50: MMP-1 > 10 μM; MMP-2 > 10 μM; MMP-3 > 2.5 μM; MMP-7 > 10 μM; MMP-8 = 7.4 nM; MMP-9 > 10 μM; MMP-12 > 10 μM; MMP-14 > 10 μM | IC50: MMP-1 > 10 μM; MMP-2 = 5.3 μM; MMP-3 = 4 μM; MMP-7 > 10 μM; MMP-8 = 720 nM; MMP-9 = 10 μM; MMP-10 = 160 nM; MMP-13 = 0.0039 nM; MMP-14 > 10 μM | |||
IC50: MMP-1 > 10 μM; MMP-2 > 2.5 μM; MMP-7 > 10 μM; MMP-8 = 57 nM; MMP-9 > 10 μM; MMP-14 > 10 μM | IC50: MMP-1 > 21.5 μM; MMP-7 > 21.5 μM; MMP-13 = 430 nM | IC50: MMP-1 > 10 μM; MMP-7 = 3.025 nM; MMP-13 = 0.5 nM | |||
IC50: MMP-1 > 22 μM; MMP-2 = 18 μM; MMP-3 > 22 μM; MMP-7 > 22μM; MMP-8 > 22 μM; MMP-9 = 8.9 μM; MMP-10 = 16 μM; MMP-12 > 22 μM; MMP-13 = 1 nM; MMP-14 = 8.3 μM | IC50: MMP-1 > 18.6 μM; MMP-7 > 18.6 μM; MMP-13 = 620 nM; MMP-14 > 62 μM | ||||
IC50: MMP-13 = 6.6 μM | Ki: MMP-2 > 3.333 μM; MMP-3 > 4.501 μM; MMP-7 > 636 nM; MMP-12 > 6.023 μM; MMP-13 = 4.314 μM | IC50: MMP-12 > 22 μM; MMP-13 > 100 μM |
Doxycycline | IC50: MMP-1 > 400 μM; MMP-7 = 28 μM; MMP-3 = 30 μM; MMP-13 = 2 μM |
CMT-1 | IC50: MMP-8 = 30 μM; MMP-13 = 1 μM |
Matastat (COL-3; CMT-3) | IC50: MMP-1 = 34 μg·mL−1; MMP-8 = 48 μg·mL−1; MMP-13 = 0.3 μg·mL−1 |
Minocycline | IC50: MMP-9 = 272 μM |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Laronha, H.; Carpinteiro, I.; Portugal, J.; Azul, A.; Polido, M.; Petrova, K.T.; Salema-Oom, M.; Caldeira, J. Challenges in Matrix Metalloproteinases Inhibition. Biomolecules 2020, 10, 717. https://doi.org/10.3390/biom10050717
Laronha H, Carpinteiro I, Portugal J, Azul A, Polido M, Petrova KT, Salema-Oom M, Caldeira J. Challenges in Matrix Metalloproteinases Inhibition. Biomolecules. 2020; 10(5):717. https://doi.org/10.3390/biom10050717
Chicago/Turabian StyleLaronha, Helena, Inês Carpinteiro, Jaime Portugal, Ana Azul, Mário Polido, Krasimira T. Petrova, Madalena Salema-Oom, and Jorge Caldeira. 2020. "Challenges in Matrix Metalloproteinases Inhibition" Biomolecules 10, no. 5: 717. https://doi.org/10.3390/biom10050717