Tyrosine Kinases As Druggable Targets In Cancer

Protein tyrosine kinase (PTK) deregulation contributes to growth of cancer and many other diseases. The development of small-molecule tyrosine kinase inhibitors (TKIs) that target the deregulated PTKs, such as epidermal growth factor receptor (EGFR) in non-small-cell lung cancer (NSCLC) and Bcr-ABL in chronic myeloid leukemia (CML), has revolutionized disease management. In this book, we examine a few aspects of PTKs and cancer, considering efficacy, predictive markers to therapeutic response, limitations, and future directions in TKI treatment. In this rapidly evolving field, overcoming therapeutic resistance is most challenging, and multi-targeting directs the next-generation TKIs and combination therapy as ongoing strategies in cancer treatment.

Leading researchers, from the Novartis group that pioneered Gleevec/GlivecTM and around the world, comprehensively survey the state of the art in the drug discovery processes (bio- and chemoinformatics, structural biology, profiling, generation of resistance, etc.) aimed at generating PTK inhibitors for the treatment of various diseases, including cancer. Highlights include a discussion of the rationale and the progress made towards generating "selective" low molecular-weight kinase inhibitors; an analysis of the normal function, role in disease, and application of platelet-derived growth factor antagonists; and a summary of the factors involved in successful structure-based drug design. Additional chapters address the advantages and disadvantages of in vivo preclinical models for testing protein kinase inhibitors with antitumor activity and the utility of different methods in the drug discovery and development process for determining "on-target" vs "off-target" effects of kinase inhibitors.

For the past two decades, the protein kinase family has been an intense area of research for developing anticancer drugs. Despite tremendous advancements in kinase drug expansion, many kinases are still unexplored. As such, this book includes research and review articles from experts that focus on protein kinase signalling pathways as a molecular drug target. Chapters include illustrations and cover such topics as the mechanism of action and anticancer activity of protein kinase inhibitors on various cancer types. They also discuss new opportunities, challenges, and future perspectives in the field.

This timely guide to kinase inhibitor drug development is the first to cover the entire drug pipeline, from target identification to compound development and clinical application. Edited by the pioneers in the field, on the drug development side this ready reference discusses classical medicinal chemistry approaches as well as current chemical genomics strategies. On the clinical side, both current and future therapeutic application areas for kinase inhibitor drugs are addressed, with a strong focus on oncology drugs. Backed by recent clinical experience with first-generation drugs in the battle against various forms of cancer, this is crucial reading for medicinal, pharmaceutical and biochemists, molecular biologists, and oncologists, as well as those working in the pharmaceutical industry.

International experts present innovative therapeutic strategies to treat cancer patients and prevent disease progression Extracellular Targeting of Cell Signaling in Cancer highlights innovative therapeutic strategies to treat cancer metastasis and prevent tumor progression. Currently, there are no drugs available to treat or prevent metastatic cancer other than non-selective, toxic chemotherapy. With contributions from an international panel of experts in the field, the book integrates diverse aspects of biochemistry, molecular biology, protein engineering, proteomics, cell biology, pharmacology, biophysics, structural biology, medicinal chemistry and drug development. A large class of proteins called kinases are enzymes required by cancer cells to grow, proliferate, and survive apoptosis (death) by the immune system. Two important kinases are MET and RON which are receptor tyrosine kinases (RTKs) that initiate cell signaling pathways outside the cell surface in response to extracellular ligands (growth factors.) Both kinases are oncogenes which are required by cancer cells to migrate away from the primary tumor, invade surrounding tissue and metastasize. MET and RON reside on both cancer cells and the support cells surrounding the tumor, called the microenvironment. MET and RON are activated by their particular ligands, the growth factors HGF and MSP, respectively. Blocking MET and RON kinase activation and downstream signaling is a promising therapeutic strategy for preventing tumor progression and metastasis. Written for cancer physicians and biologists as well as drug discovery and development teams in both industry and academia, this is the first book of its kind which explores novel approaches to inhibit MET and RON kinases other than traditional small molecule kinase inhibitors. These new strategies target key tumorigenic processes on the outside of the cell, such as growth factor activation by proteases. These unique strategies have promising potential as an improved alternative to kinase inhibitors, chemotherapy, or radiation treatment.

This book devotes a chapter to each RTK family and the multiple receptors within each family, thoroughly covering all of the RTKs. The chapters all follow the same structure, presenting this essential information in an accessible and user-friendly format. Each chapter covers one specific family of receptors and begins with a general introduction to that family and a comprehensive discussion of that receptor’s family in development and human disease. Following are in-depth analyses of each family’s receptors with discussions on the gene, protein, ligands, activation, and signaling pathways along with discussion of receptor processing and signal attenuation. Further, cross talk with other receptors systems, post-translational modification and specific unique characteristics to each RTK are discussed. Because it isolates and explains each family, this book is an essential companion volume to Receptor Tyrosine Kinases: Structure, Functions and Role in Human Disease, by the same authors, which talks about RTKs more generally and without the family-by-family detail.

An expert guide to targeting protein kinases in cancer therapy Research has shown that protein kinases can instigate the formation and spread of cancer when they transmit faulty signals inside cells. Because of this fact, pharmaceutical scientists have targeted kinases for intensive study, and have been working to develop medicinal roadblocks to sever their malignant means of communication. Complete with full-color presentations, Targeting Protein Kinases for Cancer Therapy defines the structural features of protein kinases and examines their cellular functions. Combining kinase biology with chemistry and pharmacology applications, this book enlists emerging data to drive the discovery of new cancer-fighting drugs. Valuable information includes: Comprehensive overviews of the major kinase families involved in oncology, integrating protein structure and function, and providing important tools to assist pharmaceutical researchers to understand and work in this dynamic area of cancer drug research Focus on small molecule inhibitors as well as other therapeutic modalities Discussion of kinase inhibitors that have entered clinical trials for the treatment of cancer, with an emphasis on molecules that have progressed to late stage clinical trials and, in a few cases, to market Providing a platform for further study, this important work reviews both the successes and challenges of kinase inhibitor therapy, and provides insight into future directions in the war against cancer.

Molecules Engineered Against Oncogenic Proteins and Cancer A comprehensive review of the latest molecular advances in cancer treatment Featuring 91 total small molecule kinase/KRAS inhibitors, 80 of which are FDA-approved, Molecules Engineered Against Oncogenic Proteins and Cancer documents the recent scientific advances that have transformed one of medicine’s most challenging areas—cancer treatment. Most of these inhibitors specifically block oncogene-induced carcinogenic proteins with results that have dramatically advanced the treatment of cancer. In addition, the structural formulas of more than 100 kinase/KRAS inhibitors in clinical trials are presented. With a very well-known chemist as an author, Molecules Engineered Against Oncogenic Proteins and Cancer includes information on: Each molecule’s structure, function of the kinase target and relevance to cancer, the drug discovery process, and molecular details of drug action Mutated protein kinases as oncoproteins and targets for inhibition, along with the details of discovery for each antitumor antikinase agent History of oncoprotein inhibitors and their role in advancing the treatment and understanding of cancer The discovery process as a whole, effective strategies for innovation, ongoing challenges, and a glimpse of the future of the field Combining the most significant recent discoveries in a unique and useful way, Molecules Engineered Against Oncogenic Proteins and Cancer is an essential resource for researchers and students in bioscience, medicine, chemistry, and oncology as well as for those at industrial companies involved in therapeutic discovery.