Inhibitors Of Cyclin Dependent Kinases As Anti Tumor Agents

One of the few books to cover all aspects of cyclin-dependent kinases (CDKs), Inhibitors of Cyclin-dependent Kinases as Anti-tumor Agents provides an overview of CDKs as molecular and functional entities, their involvement in different disease processes, and their potential for pharmacological modulation. With contributions from the top international researchers in the field, the book takes a contemporary approach to study the importance of rational drug design and knowledge-based therapeutics in relation to CDKs. The first two sections of the book discuss the integration of cell cycle control pathways, opportunities for targeting, targets of inhibitors, and the evaluation of CDK inhibitors, exploring topics such as the in vivo function of CDKs in normal homeostasisand tumor development and the structural biology of CDKs. The third section examines the design, development, and chemistry of small molecule CDK inhibitors, with discussions ranging from the early-stage discovery of new chemical entities with a capacity to inhibit CDKs to late-stage compounds in clinical development. The final section assesses the current status of CDK inhibitors in clinical trials, the therapeutic deployment challenges of small molecule inhibitors, and the future development of CDK inhibitors as anticancer agents. The field of drug development is at a critical point in terms of understanding the availability, advantages, and drawbacks of CDKs as therapeutic targets for small molecules. Providing the most up-to-date, in-depth coverage available in a single volume, Inhibitors of Cyclin-dependent Kinases as Anti-tumor Agents surveys the success of the agents developed thus far, the possibility of new routes to more selective inhibitors, and the growing appreciation of critical, therapeutic issues.

More than 10 years ago, the discovery of cyclin-dependent ki nases (Cdks) ushered in a new era in the understanding of cell proliferation and its control. Not only were both of the known cell cycle transitions, from G 1 to S phase and G2 to M phase, found to be dependent on these protein kinases, but the reg ulatory assumption intrinsic to cyclin-dependent kinases, a stable inactive catalytic subunit (the Cdk) and an unstable requisite positive regulatory activating subunit (the cyclin), led to a simple model for cell cycle control. Modulation of cyclin accumulation, and thereby Cdk activation, was proposed to be the overarching principle governing the passage through cell cycle phases. An other reality to emerge from the discovery of Cdks was the ex ceptional degree of evolutionary conservation maintained in the machinery and organization of proliferation control. Not only were Cdks shown to be structurally conserved between yeast and man, but mammalian Cdks could substitute functionally for the endogenous enzymes in a yeast cell. The problem of cell cycle control was thought to have been virtually solved. The ensuing years have provided a much more complex view of cell cycle control and the role and regulation of Cdks. The uncritical enthusiasm with which many of the ideas were em braced has required tempering. For example, although Cdks appear to be highly conserved phylogenetically, cyclins are much less so.

Tyrosine Kinase Inhibitors as Sensitizing Agents for Chemotherapy, the fourth volume in the Cancer Sensitizing Agents for Chemotherapy Series, focuses on strategic combination therapies that involve a variety of tyrosine kinase inhibitors working together to overcome multi-drug resistance in cancer cells. The book discusses several tyrosine kinase inhibitors that have been used as sensitizing agents, such as EGFR, BCR-ABL, ALK and BRAF. In each chapter, readers will find comprehensive knowledge on the inhibitor and its action, including its biochemical, genetic, and molecular mechanisms' emphases. This book is a valuable source for oncologists, cancer researchers and those interested in applying new sensitizing agents to their research in clinical practice and in trials. Summarizes the sensitizing role of some tyrosine kinase inhibitors in existing research Brings recent findings in several cancer types, both experimental and clinically, with a particular emphases on underlying biochemical, genetic, and molecular mechanisms Provides an updated and comprehensive knowledge regarding the field of combinational cancer treatment

Expert physician-scientists and clinicians review those combinations of novel target agents classic chemotherapies that hold the most promise for the future of medical oncology, and detail their optimal sequence, pharmacokinetic interactions, and interaction with downstream cellular signals. The combinations run the gamut of targeted therapies against cell surface receptors (EGF-R and HER2), the cell cycle (the CDKs), signal transduction events (PKC and NF-kB), apoptosis (bcl-2), as well as focused therapies in ovarian cancer, hematologic diseases, and breast cancer. The authors emphasize novel translational approaches that are rapidly moving from the laboratory bench top to the patient's bedside for the future treatments in cancer therapy.

More than 10 years ago, the discovery of cyclin-dependent ki nases (Cdks) ushered in a new era in the understanding of cell proliferation and its control. Not only were both of the known cell cycle transitions, from G 1 to S phase and G2 to M phase, found to be dependent on these protein kinases, but the reg ulatory assumption intrinsic to cyclin-dependent kinases, a stable inactive catalytic subunit (the Cdk) and an unstable requisite positive regulatory activating subunit (the cyclin), led to a simple model for cell cycle control. Modulation of cyclin accumulation, and thereby Cdk activation, was proposed to be the overarching principle governing the passage through cell cycle phases. An other reality to emerge from the discovery of Cdks was the ex ceptional degree of evolutionary conservation maintained in the machinery and organization of proliferation control. Not only were Cdks shown to be structurally conserved between yeast and man, but mammalian Cdks could substitute functionally for the endogenous enzymes in a yeast cell. The problem of cell cycle control was thought to have been virtually solved. The ensuing years have provided a much more complex view of cell cycle control and the role and regulation of Cdks. The uncritical enthusiasm with which many of the ideas were em braced has required tempering. For example, although Cdks appear to be highly conserved phylogenetically, cyclins are much less so.

Leading clinicians and investigators review in a comprehensible and user-friendly style all the latest information about the molecular biology of cell cycle control and demonstrate its clinical relevance to understanding neoplastic diseases. Topics range from Cdk inhibitors and cell cycle regulators to the prognostic value of p27 and tumor suppressor genes as diagnostic tools. Actual case studies show how the new molecular understanding has produced such drugs as Flavopiridol and Sulindac. The book brings all the recent critical research findings to bear on clinical practice, and clearly shows their powerful impact on the diagnostics, prognostics, and therapeutics of cancer, AIDS, and cardiovascular disease.

This book discusses the efficacy of various naturally occurring chemopreventive agents in preventing or delaying cancer. It focuses on the holistic chemopreventive concept, demonstrating the relevant response is the combined effect of a series of compounds that alone have been shown to have some effect in different experimental models. Written by leading experts in the field, the contributions provide details of research on various chemopreventive agents. Offering insights into the unique molecular targets and mechanisms, safety issues, molecular efficacy, and occurrence in nature of these compounds, the book is a valuable resource for all scientists working in biomedicine, and specifically in cancer research.

Discovery and Development of Anti-Breast Cancer Agents from Natural Products presents cutting-edge research advances in the field of bioactive natural products and natural drug formulations. This volume in the Natural Products Drug Discovery series focuses on molecules of natural origin and their synthetic analogs that show promising potential to act as anti-breast cancer and chemotherapeutic agents. Combining foundational background information on cancer mechanisms with details of medicinal structures from natural products, this volume compiles the latest developments from across interdisciplinary fields. Discovery and Development of Anti-Breast Cancer Agents from Natural Products will serve as a valuable resource for researchers working to discover promising leads for the development of novel pharmaceuticals for breast cancer, highlighting a number of key structures from natural products and exploring possible future developments in the area. Highlights active agents from natural sources for development as novel anti-cancer agents Features contributions from active researchers and leading experts working in the field Includes foundational background information on both breast cancer mechanisms and natural product structures to support researchers from different disciplines