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APMIS : Acta Pathologica,... Jan 1999The activation of pro matrix metalloproteinases (MMPs) by sequential proteolysis of the propeptide blocking the active site cleft is regarded as one of the key levels of... (Review)
Review
The activation of pro matrix metalloproteinases (MMPs) by sequential proteolysis of the propeptide blocking the active site cleft is regarded as one of the key levels of regulation of these proteinases. Potential physiological mechanisms including cell-associated plasmin generation by urokinase-like plasminogen activator, or the action of cell surface MT1-MMPs appear to be involved in the initiation of cascades of pro MMP activation. Gelatinase A, collagenase 3 and gelatinase B may be activated by MT-MMP based mechanisms, as evidenced by both biochemical and cell based studies. Hence the regulation of MT-MMPs themselves becomes critical to the determination of MMP activity. This includes activation, assembly at the cell surfaces as TIMP-2 complexes and subsequent inactivation by proteolysis or TIMP inhibition.
Topics: Animals; Collagenases; Enzyme Activation; Enzyme Precursors; Gelatinases; Humans; Matrix Metalloproteinase 13; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinases, Membrane-Associated; Metalloendopeptidases
PubMed: 10190278
DOI: 10.1111/j.1699-0463.1999.tb01524.x -
Trends in Pharmacological Sciences Apr 2013Matrix metalloproteinases (MMPs) are reputed to cause the inflammatory tissue destruction characterizing chronic inflammatory diseases and to degrade basement membrane... (Review)
Review
Matrix metalloproteinases (MMPs) are reputed to cause the inflammatory tissue destruction characterizing chronic inflammatory diseases and to degrade basement membrane collagen, thereby facilitating cancer cell metastasis. However, following the disappointing MMP drug cancer trials, recent studies using mouse models of disease coupled with high-throughput methods for substrate discovery have revealed surprising and unexpected new biological roles of MMPs in inflammatory diseases and cancer in vivo. Thus, MMPs modify signaling pathways and regulate the activity of whole families of cytokines of the immune response by precise proteolytic processing. By cleaving and inactivating cytokine-binding proteins and protease inhibitors, cytokine activities are unmasked and activities of diverse proteases are increased in an interconnected protease web. With new substrates come new roles, and 10 of 24 murine MMPs have antitumorigenic and anti-inflammatory roles making them drug antitargets; that is, their beneficial actions should not be inhibited. Here, we examine whether the discovery that MMPs are drug antitargets for one disease might pave the way for their use for other indications or whether this is a serious threat to the development of MMP inhibitors.
Topics: Animals; Humans; Inflammation; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Molecular Targeted Therapy; Neoplasms
PubMed: 23541335
DOI: 10.1016/j.tips.2013.02.004 -
Current Medicinal Chemistry 2008Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation and remodeling of extracellular matrix proteins that are... (Review)
Review
Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation and remodeling of extracellular matrix proteins that are associated with the tumorigenic process. MMPs promote tumor invasion and metastasis, regulating host defense mechanisms and normal cell function.Thus, MMP inhibitors (MMPIs) are expected to be useful for the treatment of diseases such as cancer, osteoarthritis, and rheumatoid arthritis. A vast number of MMPIs have been developed in recent years. With the failure of these inhibitors in clinical trials,more efforts have been directed to the design of specific inhibitors with different Zn-binding groups. This review summarizes the current status of MMPIs, the design of small molecular weight MMPIs , a brief description of available three-dimensional MMP structures, a review of the proposed therapeutic utility of MMPIs, and a clinical update of compounds that have entered clinical trials in humans.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Drug Design; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Molecular Conformation; Molecular Structure; Neoplasms; Protease Inhibitors
PubMed: 18537616
DOI: 10.2174/092986708784567680 -
Current Pharmaceutical Design 2013This review highlights some recent advances in the design and development of matrix metalloproteinase inhibitors, especially those targeting MMP-2, MMP-9, and MMP-13.... (Review)
Review
This review highlights some recent advances in the design and development of matrix metalloproteinase inhibitors, especially those targeting MMP-2, MMP-9, and MMP-13. Various zinc-binding groups and non-zinc-binding groups are discussed. Interactions between residues in the critical S1' specificity pocket and MMP inhibitors are given special attention. The influence of ionization states of hydroxamates and retrohydroxamates on the docking outcome and the presence of zinc ions in the active site are explored in light of enhancing enrichment factors for docking studies. Details are given to structural factors for the development of more selective and more potent MMP inhibitors.
Topics: Amino Acid Sequence; Matrix Metalloproteinases; Molecular Sequence Data; Protease Inhibitors; Sequence Homology, Amino Acid
PubMed: 23260023
DOI: 10.2174/1381612811319260004 -
Cancer Metastasis Reviews Dec 2014Heightened matrix metalloproteinase (MMP) activity has been noted in the context of the tumor microenvironment for many years, and causal roles for MMPs have been... (Review)
Review
Heightened matrix metalloproteinase (MMP) activity has been noted in the context of the tumor microenvironment for many years, and causal roles for MMPs have been defined across the spectrum of cancer progression. This is primarily due to the ability of the MMPs to process extracellular matrix (ECM) components and to regulate the bioavailability/activity of a large repertoire of cytokines and growth factors. These characteristics made MMPs an attractive target for therapeutic intervention but notably clinical trials performed in the 1990s did not fulfill the promise of preclinical studies. The reason for the failure of early MMP inhibitor (MMPI) clinical trials that are multifold but arguably principal among them was the inability of early MMP-based inhibitors to selectively target individual MMPs and to distinguish between MMPs and other members of the metzincin family. In the decades that have followed the MMP inhibitor trials, innovations in chemical design, antibody-based strategies, and nanotechnologies have greatly enhanced our ability to specifically target and measure the activity of MMPs. These advances provide us with the opportunity to generate new lines of highly selective MMPIs that will not only extend the overall survival of cancer patients, but will also afford us the ability to utilize heightened MMP activity in the tumor microenvironment as a means by which to deliver MMPIs or MMP activatable prodrugs.
Topics: Carcinogenesis; Extracellular Matrix; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Tumor Microenvironment
PubMed: 25325988
DOI: 10.1007/s10555-014-9530-4 -
Current Medicinal Chemistry 2005The matrix metalloproteinases (MMPs) are a family of more than 20 enzymes that are intimately involved in tissue remodelling. These zinc-containing endopeptidases... (Review)
Review
The matrix metalloproteinases (MMPs) are a family of more than 20 enzymes that are intimately involved in tissue remodelling. These zinc-containing endopeptidases consist of several subsets of enzymes, including collagenase, stromelysins and gelatinases and are involved in the degradation of the extracellullar matrix (ECM) that forms the connective material between cells and around tissues. Disease processes associated with the MMPs are generally related to imbalance between the inhibition and activation of MMPs resulting in excessive degradation of the ECM. These indications include osteoarthritis rheumatoid arthritis, tumour metastasis and congestive heart failure. Inhibitors for these enzymes have been developed for the treatment of a starthingly wide array of disease process where matrix remodelling plays a key role. There are three major components to most MMP inhibitors- the zinc binding group ZBG, the peptidic backbone and the pocket occupying side chain. Most MMPs inhibitors are classified according to their ZBG. Inhibitors interactions at active-site zinc plays a critical role in defining the binding mode and relative inhibitor potency. The majority of MMP inhibitors reported in the literature contain an effective zinc binding group (e.g. hydroxamic acid, carboxylic acid, sulfhydryl group) that is either generally substituted with a peptide-like structure that mimics the substrates that they cleave or appended to smaller side chains that may interact with specific subsites (e.g., P1', P2', P3') within the active site. Although carboxylates exhibit weaker zinc binding properties than hydroxamates, they are known to show better oral bioavailability and are less prone to metabolic degradation. The expected loss of binding affinity after replacement of hydroxamates against carboxylates is faced by adequate choice of elongated S1' directed substituents. The need for novel selective MMP inhibitors makes them an attractive target for the QSAR and molecular modelling. 3-D QSAR models were derived using CoMFA, CoMSIA and GRID approaches leading to the identification of binding regions where steric, electronic or hydrophobic effects are important for affinity. Some structural requirements essential for achieving high binding affinity and selectivity are: an acidic unit tightly anchored through four contact points, bidentate chelation of Zn2+, carbonyl groups for hydrogen bonding, more than two extra units for hydrogen bonds, a hydrophobic moiety.
Topics: Binding Sites; Enzyme Inhibitors; Extracellular Matrix; Hydroxamic Acids; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Molecular Conformation; Molecular Structure; Quantitative Structure-Activity Relationship; Structure-Activity Relationship; Substrate Specificity
PubMed: 15723623
DOI: 10.2174/0929867053363243 -
Biochimica Et Biophysica Acta Jan 2010
Topics: Animals; Clinical Trials as Topic; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasms; Protease Inhibitors; Substrate Specificity
PubMed: 20159302
DOI: 10.1016/j.bbamcr.2010.01.016 -
Expert Opinion on Investigational Drugs May 2000The activity of matrix-degrading metalloproteinases (MMPs) is essential for many of the processes involved in atherosclerotic plaque formation, for example, infiltration... (Review)
Review
The activity of matrix-degrading metalloproteinases (MMPs) is essential for many of the processes involved in atherosclerotic plaque formation, for example, infiltration of inflammatory cells, smooth muscle cell migration and proliferation and angiogenesis. Furthermore, matrix degradation by MMPs may cause the plaque instability and rupture that leads to the clinical symptoms of atherosclerosis; unstable angina, myocardial infarction and stroke. Together, the family of MMPs can degrade all of the components of the blood vessel extracellular matrix and their activity therefore, is tightly regulated in normal blood vessels. The increased MMP activity during atherosclerotic plaque development and instability must therefore be caused by increased cytokine and growth factor-stimulated gene transcription, elevated zymogen activation and an imbalance in the MMP:TIMP ratio. It is therefore conceivable that inhibition of MMPs or re-establishing the MMP:TIMP balance may be useful in treating the symptoms of atherosclerosis. Recent studies using synthetic MMP inhibitors and gene therapy have highlighted the potential of such an approach.
Topics: Animals; Arteriosclerosis; Enzyme Inhibitors; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Tissue Inhibitor of Metalloproteinases
PubMed: 11060722
DOI: 10.1517/13543784.9.5.993 -
Influence of matrix metalloproteinase genotype on cardiovascular disease susceptibility and outcome.Cardiovascular Research Feb 2006Data have been accumulating that indicate that matrix metalloproteinase (MMP) gene polymorphisms contribute to inter-individual differences in susceptibility to and... (Review)
Review
Data have been accumulating that indicate that matrix metalloproteinase (MMP) gene polymorphisms contribute to inter-individual differences in susceptibility to and outcome of cardiovascular disease. This is currently best exemplified by the MMP3 gene 5A/6A polymorphism which has an effect on MMP3 expression and has been shown to be associated with coronary stenosis, myocardial infarction, coronary artery calcification, post-angioplasty coronary restenosis, carotid atherosclerosis, stroke, arterial stiffness, and blood pressure. Functional polymorphisms in the MMP1, MMP2, MMP7, MMP9, MMP12, and MMP13 genes have also been related to coronary artery disease, arterial stiffness, and/or abdominal aortic aneurysm. These genetic findings support the notion that MMPs play important roles in the pathogenesis of these conditions. There is also some evidence suggesting that MMP genotyping could aid in identifying patients who are likely to have unfavourable prognosis and/or adverse response to treatment.
Topics: Cardiovascular Diseases; Cardiovascular System; Genetic Predisposition to Disease; Genotype; Heterozygote; Humans; Matrix Metalloproteinases; Treatment Outcome
PubMed: 16122719
DOI: 10.1016/j.cardiores.2005.07.015 -
Current Drug Targets. Inflammation and... Jun 2005The matrix metalloproteinases (MMPs) comprise a family of enzymes that collectively can degrade all components of the extracellular matrix (ECM). MMPs play an important... (Review)
Review
The matrix metalloproteinases (MMPs) comprise a family of enzymes that collectively can degrade all components of the extracellular matrix (ECM). MMPs play an important role in many physiological processes such as embryonic development and growth, tissue remodelling and repair. Overexpression and activation of MMPs contributes to many pathologies, including arthritis, cardiovascular disease, tumour progression and lung disease. Targeted mutagenesis has allowed investigators to examine the contribution of MMPs to these physiological and pathologic processes. In this manuscript, we will present an up-to date review of these studies. Rheumatoid arthritis (RA) and osteoarthritis (OA) are chronic diseases that result in cartilage degradation and loss of joint function. MMPs have been implicated in the collagen breakdown that contributes to joint destruction. Current available drugs to treat arthritis are predominantly directed towards the control of pain and/or the inflammation associated with joint synovitis but they do little to reduce joint destruction. Synthetic MMP inhibitors have been developed and in animal models of OA and/or RA, these agents have shown chondroprotective effects. However, results from clinical trials in RA have been equivocal, with some studies being terminated because of lack of efficacy or safety concerns. Increased understanding of the structure, regulation and function of individual MMPs may lead to more effective strategies. Approaches aimed at multiple steps of the pathogenesis of arthritis may be needed to break the chronic cycle of joint destruction. In the future, it will be important to have drugs that prevent the structural damage caused by bone and cartilage breakdown.
Topics: Animals; Connective Tissue; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Mice, Knockout; Protease Inhibitors; Rheumatic Diseases
PubMed: 16101546
DOI: 10.2174/1568010054022141