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International Journal of Molecular... Jul 2023Matrix metalloproteinases (MMPs) belong to a family of zinc-dependent proteolytic metalloenzymes. MMP-9, a member of the gelatinase B family, is characterized as one of... (Review)
Review
Matrix metalloproteinases (MMPs) belong to a family of zinc-dependent proteolytic metalloenzymes. MMP-9, a member of the gelatinase B family, is characterized as one of the most intricate MMPs. The crucial involvement of MMP-9 in extracellular matrix (ECM) remodeling underscores its significant correlation with each stage of cancer pathogenesis and progression. The design and synthesis of MMP-9 inhibitors is a potentially attractive research area. Unfortunately, to date, there is no effective MMP-9 inhibitor that passes the clinical trials and is approved by the FDA. This review primarily focuses on exploring the diverse strategies employed in the design and advancement of MMP-9 inhibitors, along with their anticancer effects and selectivity. To illuminate the essential structural characteristics necessary for the future design of novel MMP-9 inhibitors, the current narrative review highlights several recently discovered MMP-9 inhibitors exhibiting notable selectivity and potency.
Topics: Humans; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Neoplasms; Matrix Metalloproteinases; Proteolysis; Extracellular Matrix
PubMed: 37569509
DOI: 10.3390/ijms241512133 -
Pharmacological Research Feb 2020Idiopathic pulmonary fibrosis (IPF) is a debilitating condition where excess collagen deposition occurs in the extracellular matrix. At first sight, it is expected that... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a debilitating condition where excess collagen deposition occurs in the extracellular matrix. At first sight, it is expected that the level of different kinds of matrix metalloproteinases might be downregulated in IPF as it is a matrix degrading collagenase. However, the role of some matrix metalloproteinases (MMPs) is profibrotic where others have anti-fibrotic functions. These profibrotic MMPs effectively promote fibrosis development by stimulating the process of epithelial to mesenchymal transition. These profibrotic groups also induce macrophage polarization and fibrocyte migration. All of these events ultimately disrupt the balance between profibrotic and antifibrotic mediators, resulting aberrant repair process. Therefore, inhibition of these matrix metalloproteinases functions in IPF is a potential therapeutic approach. In addition to the use of synthetic inhibitor, various natural compounds, gene silencing act as potential natural MMP inhibitor to recover IPF.
Topics: Animals; Humans; Idiopathic Pulmonary Fibrosis; Lung; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases
PubMed: 31837390
DOI: 10.1016/j.phrs.2019.104591 -
Current Pharmaceutical Biotechnology 2021Matrix Metalloproteinases (MMPs), as a family of zinc-containing enzymes, show the function of decomposing Extracellular Matrix (ECM) and participate in the... (Review)
Review
Matrix Metalloproteinases (MMPs), as a family of zinc-containing enzymes, show the function of decomposing Extracellular Matrix (ECM) and participate in the physiological processes of cell migration, growth, inflammation, and metabolism. Clinical and experimental studies have indicated that MMPs play an essential role in tissue injury and repair as well as tumor diagnosis, metastasis, and prognosis. An increasing number of researchers have paid attention to their functions and mechanisms in bone health and diseases. The present review focuses on MMPs-inspired therapeutic strategies for the treatment of bone-related diseases. We introduce the role of MMPs in bone diseases, highlight the MMPs-inspired therapeutic options, and posit MMPs as a trigger for smart cell/drug delivery.
Topics: Animals; Bone Diseases; Extracellular Matrix; Humans; Matrix Metalloproteinases
PubMed: 32603279
DOI: 10.2174/1389201021666200630140735 -
Pharmacological Reviews Jul 2022The first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, matrix... (Review)
Review
The first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, matrix metalloproteinases are proteases capable of remodeling the extracellular matrix. More recently, MMPs have been demonstrated to play numerous additional biologic roles in cell signaling, immune regulation, and transcriptional control, all of which are unrelated to the degradation of the extracellular matrix. In this review, we will present milestones and major discoveries of MMP research, including various clinical trials for the use of MMP inhibitors. We will discuss the reasons behind the failures of most MMP inhibitors for the treatment of cancer and inflammatory diseases. There are still misconceptions about the pathophysiological roles of MMPs and the best strategies to inhibit their detrimental functions. This review aims to discuss MMPs in preclinical models and human pathologies. We will discuss new biochemical tools to track their proteolytic activity in vivo and ex vivo, in addition to future pharmacological alternatives to inhibit their detrimental functions in diseases. SIGNIFICANCE STATEMENT: Matrix metalloproteinases (MMPs) have been implicated in most inflammatory, autoimmune, cancers, and pathogen-mediated diseases. Initially overlooked, MMP contributions can be both beneficial and detrimental in disease progression and resolution. Thousands of MMP substrates have been suggested, and a few hundred have been validated. After more than 60 years of MMP research, there remain intriguing enigmas to solve regarding their biological functions in diseases.
Topics: Extracellular Matrix; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasms; Proteolysis
PubMed: 35738680
DOI: 10.1124/pharmrev.121.000349 -
Molecular Biology Reports Sep 2021Matrix metalloproteinases (MMPs) or matrixins, are members of a zinc-dependent endopeptidase family. They cause remodeling of the extracellular matrix (ECM) leading to... (Review)
Review
Matrix metalloproteinases (MMPs) or matrixins, are members of a zinc-dependent endopeptidase family. They cause remodeling of the extracellular matrix (ECM) leading to numerous diseases. MMPs subfamilies possess: collagenases, gelatinases, stromelysins and membrane-type MMPs (MT-MMP). They consist of several domains; pro-peptide, catalytic, linker peptide and the hemopexin (Hpx) domains. MMPs are involved in initiation, proliferation and metastasis of cancer through the breakdown of ECM physical barriers. Overexpression of MMPs is associated with poor prognosis of cancer. This review will discuss both types of MMPs and current inhibitors, which target them in different aspects, including, biosynthesis, activation, secretion and catalytic activity. Several synthetic and natural inhibitors of MMPs (MMPIs) that can bind the catalytic domain of MMPs have been designed including; peptidomimetic, non-peptidomimetic, tetracycline derivatives, off-target MMPI, natural products, microRNAs and monoclonal antibodies.
Topics: Cell Proliferation; Drug Delivery Systems; Extracellular Matrix; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasm Metastasis; Neoplasms; Prognosis; Protein Domains
PubMed: 34379286
DOI: 10.1007/s11033-021-06635-z -
Current Medicinal Chemistry 2010Matrix metalloproteinases (MMPs), also known as matrixins, belong to a group of zinc-dependent proteins, which are thought to play a central role in the breakdown of... (Review)
Review
Matrix metalloproteinases (MMPs), also known as matrixins, belong to a group of zinc-dependent proteins, which are thought to play a central role in the breakdown of extracellular matrix. Collagen, elastin, gelatin and casein are major components cleaved by MMPs. The breakdown of these components is essential for many physiological processes such as embryonic development, morphogenesis, reproduction, and tissue resorption and remodelling. MMPs also participate in pathological processes such as arthritis, cancer, cardiovascular and neurological diseases. This review summarizes current knowledge regarding these proteins, their participation in physiological and pathophysiological roles, their involvement in activation and inhibition, and their interactions with other metal-binding proteins including metallothioneins.
Topics: Cardiovascular Diseases; Cysteine; Extracellular Matrix; Gene Expression Regulation, Enzymologic; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasms; Substrate Specificity; Tissue Inhibitor of Metalloproteinases; Zinc Compounds
PubMed: 20846107
DOI: 10.2174/092986710793213724 -
Current Oncology Reports Mar 2004Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that are associated with the tumorigenic process. MMPs degrade the extracellular matrix,... (Review)
Review
Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that are associated with the tumorigenic process. MMPs degrade the extracellular matrix, promoting tumor invasion and metastasis. They also regulate host defense mechanisms and normal cell function; blocking all MMPs may not lead to a positive therapeutic outcome. Most clinical trials of MMP inhibitors (MMPIs) have yielded disappointing results, perhaps due to inappropriate study design or tumor staging, or to lack of selectivity. Positive results have been seen in gastric cancer with marimastat and in Kaposi's sarcoma with metastat. This review summarizes the current status of MMPIs.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Enzyme Inhibitors; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasms; Protease Inhibitors; Treatment Outcome
PubMed: 14751086
DOI: 10.1007/s11912-004-0020-7 -
Molecules (Basel, Switzerland) Jun 2019The family of matrix metalloproteinases (MMPs) consists of a set of biological targets that are involved in a multitude of severe pathogenic events such as different... (Review)
Review
The family of matrix metalloproteinases (MMPs) consists of a set of biological targets that are involved in a multitude of severe pathogenic events such as different forms of cancers or arthritis. Modulation of the target class with small molecule drugs has not led to the anticipated success until present, as all clinical trials failed due to unacceptable side effects or a lack of therapeutic outcome. Monoclonal antibodies offer a tremendous therapeutic potential given their high target selectivity and good pharmacokinetic profiles. For the treatment of a variety of diseases there are already antibody therapies available and the number is increasing. Recently, several antibodies were developed for the selective inhibition of single MMPs that showed high potency and were therefore investigated in in vivo studies with promising results. In this review, we highlight the progress that has been achieved toward the design of inhibitory antibodies that successfully modulate MMP-9 and MMP-14.
Topics: Amino Acid Sequence; Animals; Antibodies, Monoclonal; Binding Sites; Drug Design; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Binding; Structure-Activity Relationship
PubMed: 31216704
DOI: 10.3390/molecules24122265 -
Expert Opinion on Drug Discovery Jan 2021Matrix metalloproteinases have been in the scope of pharmaceutical drug discovery for decades as promising targets for drug development. Until present, no modulator of... (Review)
Review
INTRODUCTION
Matrix metalloproteinases have been in the scope of pharmaceutical drug discovery for decades as promising targets for drug development. Until present, no modulator of the enzyme class survived clinical trials, all failing for various reasons. Nevertheless, the target family did not lose its attractiveness and there is ever more evidence that MMP modulators are likely to overcome the hurdles and result in successful clinical therapies.
AREAS COVERED
This review provides an overview of past efforts that were taken in the development of MMP inhibitors and insight into promising strategies that might enable drug discovery in the field in the future. Small molecule inhibitors as well as biomolecules are reviewed.
EXPERT OPINION
Despite the lack of successful clinical trials in the past, there is ongoing research in the field of MMP modulation, proving the target class has not lost its appeal to pharmaceutical research. With ever-growing insights from different scientific fields that shed light on previously unknown correlations, it is now time to use synergies deriving from biological knowledge, chemical structure generation, and clinical application to reach the ultimate goal of bringing MMP derived drugs on a broad front for the benefit of patients into therapeutic use.
Topics: Animals; Drug Design; Drug Development; Drug Discovery; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Molecular Targeted Therapy
PubMed: 32921161
DOI: 10.1080/17460441.2020.1819235 -
Molecular Cancer Therapeutics Jun 2018The matrix metalloproteinases (MMP) are a family of proteolytic enzymes that degrade multiple components of the extracellular matrix. A large body of experimental and... (Review)
Review
The matrix metalloproteinases (MMP) are a family of proteolytic enzymes that degrade multiple components of the extracellular matrix. A large body of experimental and clinical evidence has implicated MMPs in tumor invasion, neoangiogenesis, and metastasis, and therefore they represent ideal pharmacologic targets for cancer therapy. From the 1990s to early 2000s, synthetic inhibitors of MMPs (MMPI) were studied in various cancer types. Unexpectedly, despite strongly promising preclinical data, all trials were unsuccessful in reducing tumor burden or improving overall survival; in addition, MMPIs had unforeseen, severe side effects. Two main reasons can explain the failure of MMPIs in clinical trials. It has now become apparent that some MMPs have antitumor effects; therefore, the broad-spectrum MMPIs used in the initial trials might block these MMPs and result in tumor progression. In addition, although MMPs are involved in the early stages of tumor progression, MMPIs were tested in patients with advanced disease, beyond the stage when these compounds could be effective. As more specific MMPIs are now available, MMP targeting could be reconsidered for cancer therapy; however, new trials should be designed to test their antimetastatic properties in early-stage tumors, and endpoints should focus on parameters other than decreasing metastatic tumor burden. .
Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Disease Progression; Disease Susceptibility; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Molecular Targeted Therapy; Neoplasms; Treatment Outcome
PubMed: 29735645
DOI: 10.1158/1535-7163.MCT-17-0646