Protein Tyrosine Kinases: From Inhibitors to Useful Drugs (Cancer Drug Discovery and Development)

Protein kinases function as components of signal transduction pathways, playing a central role in the control of cell growth, metabolism, differentiation, and apoptosis. The development of selective protein tyrosine kinase (PTK) inhibitors that can block or modulate diseases, such as cancer, with abnormalities in these signaling pathways is considered a promising approach for drug development. Currently, more than 20 different PTKs are being considered as potential therapeutic targets in oncology. In Protein Tyrosine Kinases: From Inhibitors to Useful Drugs, leading researchers from the Novartis group that pioneered Gleevec/GlivecTM and from 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 toward 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 PTK 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. Authoritative and state-of-the-art, Protein Tyrosine Kinases: From Inhibitors to Useful Drugs details the key stages in the design of PTK inhibitors and their development into useful drugs.

Protein kinases function as components of signal transduction pathways, playing a central role in the control of cell growth, metabolism, differentiation, and apoptosis. The development of selective protein tyrosine kinase (PTK) inhibitors that can block or modulate diseases, such as cancer, with abnormalities in these signaling pathways is considered a promising approach for drug development. Currently, more than 20 different PTKs are being considered as potential therapeutic targets in oncology. In Protein Tyrosine Kinases: From Inhibitors to Useful Drugs, leading researchers from the Novartis group that pioneered Gleevec/Glivec™ and from 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 toward 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 PTK 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.

Authoritative and state-of-the-art, Protein Tyrosine Kinases: From Inhibitors to Useful Drugs details the key stages in the design of PTK inhibitors and their development into useful drugs.

Protein tyrosine kinases as targets for cancer and other indications / Mark Pearson, Carlos Garcia-Echeverria, Doriano Fabbro -- Inhibitors of signaling interfaces: targeting Src homology 2 domains in drug discovery / Carlos Garcia-Echeverria -- PI 3-kinase inhibition: a target for therapeutic intervention / Peter M. Finan, Stephen G. Ward -- Src as a target for pharmaceutical intervention: potential and limitations / Mira Susa ... [et al.] -- Activated FLT3 receptor tyrosine kinase as a therapeutic target in leukemia / Blanca Scheijen, James D. Griffin -- JAK kinases in leukemias/lymphomas and multiple myeloma / Renate Burger, Martin Gramatzki -- Glivec (Gleevec, Imatinib, STI571): a targeted therapy for CML / Elisabeth Buchdunger, Renaud Capedeville -- Platelet-derived growth factor: normal function, role in disease, and applications of PDGF antagonists / Tobias Sjoblom ... [et al.] -- Structural biology of protein tyrosine kinases / Sandra W. Cowan-Jacob ... [et al.] -- Testing of signal transduction inhibitors in animal models of cancer / Terence O'Reilly, Robert Cozens -- Phosphoproteomics in drug discovery and development / Michel F. Moran 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. Front Matter....Pages i-xiii Protein Tyrosine Kinases as Targets for Cancer and Other Indications....Pages 1-29 Inhibitors of Signaling Interfaces....Pages 31-52 PI3-Kinase Inhibition....Pages 53-69 Src as a Target for Pharmaceutical Intervention....Pages 71-92 Activated FLT3 Receptor Tyrosine Kinase as a Therapeutic Target In Leukemia....Pages 93-113 JAK Kinases in Leukemias, Lymphomas, and Multiple Myeloma....Pages 115-144 Glivec® (Gleevec®, Imatinib, STI571)....Pages 145-160 Platelet-Derived Growth Factor....Pages 161-186 Structural Biology of Protein Tyrosine Kinases....Pages 187-230 Testing of Signal Transduction Inhibitors in Animal Models of Cancer....Pages 231-264 Phosphoproteomics in Drug Discovery and Development....Pages 265-278 Back Matter....Pages 279-290 In this title, leading researchers, from the Novartis group that pioneered Gleevec/Gliveca 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-deriv