Cutting-edge investigators review the current status of the entire field, from the biology of MMPs through the current clinical studies. The authors include many leading scientists from pharmaceutical companies who present all the latest concepts and results on the preferred design strategies for MMP inhibitors, their molecular mechanisms, and their substrates. In addition, they fully describe their personal research on specific MMP inhibitors, detailing vanguard design strategies, their in vitro activity, the outcome of animal model studies and, where available, their toxicology, safety, efficacy in human clinical trials. Comprehensive and state-of-the-art, Matrix Metalloproteinase Inhibitors in Cancer Therapy offers basic and clinical investigators alike a richly informative summary of all the latest research on these powerful new drugs, and their high promise as emerging cancer therapeutics.

The association of matrix metalloproteinases (MMPs)-enzymes that disrupt the body's normal repair functions-with several diseases, including growing and invasive tumors, holds the tantalizing promise that their inhibiton might have therapeutic value. In Matrix Metalloproteinase Inhibitors in Cancer Therapy, cutting-edge investigators review the current status of the entire field, from the biology of MMPs through the current clinical studies. The authors include many leading scientists from pharmaceutical companies who present all the latest concepts and results on the preferred design strategies for MMP inhibitors, their molecular mechanisms, and their substrates. In addition, they fully describe their company's research effort on specific MMP inhibitors, detailing vanguard design strategies, their in vitro activity, the outcome of animal model studies and, where available, their toxicology, safety, and efficacy in human clinical trials. Comprehensive and state-of-the-art, Matrix Metalloproteinase Inhibitors offers basic and clinical investigators alike a richly informative summary of all the latest research on these powerful new drugs, and their high promise as emerging cancer therapeutics.

Matrix Metalloproteinases (MMPs), a family of over 20 types of enzymes, collectively are capable of degrading all the components of the extracellular matrix. MMP-2 and MMP-9 (also known as gelatinases) are specifically thought to play critical roles in tumor cell invasion and are frequently co-expressed in breast cancer. Cyclic peptides containing the sequence HWGF have been described as selective inhibitors of MMP-2 and MMP-9. We tested the hypothesis that gelatinase expression may provide a target for in vivo tumor imaging using a radiolabeled gelatinase inhibitor. The peptide, DOTA-CTTHWGFTLC (DOTA-CTT), was labeled with Cu-64 T 1/2 1/2% = l2.7 h.%, which has a decay scheme suitable for both PET imaging and cancer therapy. This conjugate maintained MMP-2 inhibitory activity comparable to %Ilomastat, a broad-range inhibitor of MMPs. An increase in the MMP-2/9 activity of human metastatic breast cancer MDA-MB-435 tumors in nude mice was observed from 4 to 10 weeks post-implantation. MicroPET images of Cu-64-DOTA-CTT in the tumor-bearing nude mice showed tumor uptake at 8-wk post-implantation; however, the same mouse with 5-wk palpable tumors showed no uptake of the tracer, suggesting that the MMP-2 and MMP-9 activity is related to the stage of tumor growth. These data suggest the potential of radiolabeled gelatinase inhibitors as markers for imaging the metastatic capability of human breast cancer.

Cell Surface Proteases provides a comprehensive overview of these important enzymes that catalyze the hydrolysis of a protein as it degrades to a simpler substance. In the 1990s, an explosion of new discoveries shed light on the role of cell surface proteases and extended it beyond degradation of extracellular matrix components to include its influence on growth factors, cell signaling, and other cellular events. This volume unites the scientific literature from across disciplines and teases out unified themes of interactions between cell surface proteases and interconnecting cell surface-related systems -- including integrins and other adhesion molecules. Scientists and students involved in developmental biology, cell biology and disease processes will find this an indispensable resource. * Provides an overview of the entire field of cell surface proteases in a single volume* Presents major issues and astonishing discoveries at the forefront of modern developmental biology and developmental medicine * A thematic volume in the longest-running forum for contemporary issues in developmental biology with over 30 years of coverage

Medicinal Chemistry of Anticancer Drugs, Second Edition, provides an updated treatment from the point of view of medicinal chemistry and drug design, focusing on the mechanism of action of antitumor drugs from the molecular level, and on the relationship between chemical structure and chemical and biochemical reactivity of antitumor agents. Antitumor chemotherapy is a very active field of research, and a huge amount of information on the topic is generated every year. Cytotoxic chemotherapy is gradually being supplemented by a new generation of drugs that recognize specific targets on the surface or inside cancer cells, and resistance to antitumor drugs continues to be investigated. While these therapies are in their infancy, they hold promise of more effective therapies with fewer side effects. Although many books are available that deal with clinical aspects of cancer chemotherapy, this book provides a sorely needed update from the point of view of medicinal chemistry and drug design. Presents information in a clear and concise way using a large number of figures Historical background provides insights on how the process of drug discovery in the anticancer field has evolved Extensive references to primary literature

Of the thousands of novel compounds that a drug discovery project team invents and that bind to the therapeutic target, typically only a fraction of these have sufficient ADME/Tox properties to become a drug product. Understanding ADME/Tox is critical for all drug researchers, owing to its increasing importance in advancing high quality candidates to clinical studies and the processes of drug discovery. If the properties are weak, the candidate will have a high risk of failure or be less desirable as a drug product. This book is a tool and resource for scientists engaged in, or preparing for, the selection and optimization process. The authors describe how properties affect in vivo pharmacological activity and impact in vitro assays. Individual drug-like properties are discussed from a practical point of view, such as solubility, permeability and metabolic stability, with regard to fundamental understanding, applications of property data in drug discovery and examples of structural modifications that have achieved improved property performance. The authors also review various methods for the screening (high throughput), diagnosis (medium throughput) and in-depth (low throughput) analysis of drug properties. Serves as an essential working handbook aimed at scientists and students in medicinal chemistry Provides practical, step-by-step guidance on property fundamentals, effects, structure-property relationships, and structure modification strategies Discusses improvements in pharmacokinetics from a practical chemist's standpoint

Matrix metalloproteinases (MMPs) are proteolytic enzymes that are involved in many physiological and pathological processes. The field of MMP research is very important due to the implications of the distinct paralogs in both human physiology and pathology. Over-activation of these enzymes results in tissue degradation, producing a wide array of disease processes such as rheumatoid arthritis, osteoarthritis, tumor growth and metastasis, multiple sclerosis, congestive heart failure, and others. Thus MMP inhibitors are candidates for therapeutic agents to combat a number of diseases. The present book discusses the design and development of different classes of inhibitors of important classes of MMPs, such as gelatinases and collagenases. The articles focus specifically on structure-activity relationships of all classes of compounds and on their modes of action and specificity of binding with the receptors based on experimental and theoretical studies. These studies constitute a valuable asset for all those involved in drug development.