Protein Kinases as Drug Targets (eBook, PDF)

• Format: PDF

Produktbeschreibung

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.

Produktdetails

• Verlag: Wiley-VCH
• Seitenzahl: 396
• Erscheinungstermin: 13. Juni 2011
• Englisch
• ISBN-13: 9783527633487
• Artikelnr.: 37360677

Autorenporträt

Bert Klebl is an expert in small molecule based drug discovery. Currently, he is managing director and CSO of Lead Discovery Center GmbH, which was started by Max-Planck Innovation and the Max-Planck Society. Before, he was at GPC Biotech, Axxima Pharmaceuticals and Aventis (Hoechst Marion Roussel). A biochemist by training, he graduated from the University of Konstanz, Germany, and did post-doctoral work at the Biotechnology Research Institute in Montréal, Canada. Gerhard Müller received his PhD in Organic Chemistry in 1992 from the Technical University of Munich, working with Horst Kessler. After two years in the Medicinal Chemistry Department of Glaxo Verona (Italy), he joined the Central Research Facility of Bayer AG in Leverkusen. From 2001 to 2003 he headed the chemistry department of Organon's Lead Discovery Unit is Oss, Netherlands. In 2003 he was nominated CSO of Axxima Pharmaceuticals AG in Munich, and upon its acquisition through GPC Biotech AG in 2005, he became GPC's Vice President Drug Discovery. Since 2008 he is CSO and Managing Director of Proteros Fragments GmbH, specializing in fragment-based lead generation. Apart from numerous scientific articles and patents, he co-edited the "Chemogenomics in Drug Discovery" book of this series on medicinal chemistry. Michael Hamacher studied biology at the Heinrich-Heine-Universität in Düsseldorf, Germany. Subsequent to his PhD, he joined the Medizinisches Proteom-Center, Ruhr-Universität Bochum, Germany, and became Head of Administration of the MPC, responsible for the implementation and the strategical planning of the Human Brain Proteome Project under the roof of the Human Proteome Organisation (HUPO BPP) among others. In 2008, he moved to the Lead Discovery Center GmbH, Dortmund, Germany, for the same position, focussing on preparing national as well as international funding applications, on project management, budgeting as well as human resources. He applied and implemented numerous projects in early pharmaceutical research.

Inhaltsangabe

Preface PART I: Hit Finding and Profiling for Protein Kinases: Assay Development and Screening, Libraries IN VITRO CHARACTERIZATION OF SMALL-MOLECULE KINASE INHIBITORS Introduction Optimization of a Biochemical Kinase Assay Measuring the Binding Affinity and Residence Time of Unusual Kinase Inhibitors Addressing ADME Issues of Protein Kinase Inhibitors in Early Drug Discovery SCREENING FOR KINASE INHIBITORS: FROM BIOCHEMICAL TO CELLULAR ASSAYS Introduction Factors that Influence Cellular Efficacy of Kinase Inhibitors Assays for Measurement of Cellular Kinase Activity Outlook DISSECTING PHOSPHORYLATION NETWORKS: THE USE OF ANALOGUE-SENSITIVE KINASES AND MORE SPECIFIC KINASE INHIBITORS AS TOOLS Introduction Chemical Genetics The Application of ASKA Technology in Molecular Biology Conclusions and Outlook PART II: Medicinal Chemistry RATIONAL DRUG DESIGN OF KINASE INHIBITORS FOR SIGNAL TRANSDUCTION THERAPY The Concept of Rational Drug Design 3D Structure-Based Drug Design Ligand-Based Drug Design Target Selection and Validation Personalized Therapy with Kinase Inhibitors The NCLtm Technology and Extended Pharmacophore Modeling (Prediction-Oriented QSAR) Non-ATP Binding Site-Directed or Allosteric Kinase Inhibitors The Master Keys for Multiple Target Kinase Inhibitors Conclusions KINASE INHIBITORS IN SIGNAL TRANSDUCTION THERAPY VEGFR (Vascular Endothelial Growth Factor Receptor) Flt3 (FMS-Like Tyrosine Kinase 3) Bcr-Abl (Breakpoint Cluster Region-Abelson Murine Leukemia Viral Oncogene Homologue) EGFR (Epidermal Growth Factor Receptor) IGFR (Insulin-Like Growth Factor Receptor) FGFR (Fibroblas Growth Factor Receptor) PDGFR (Platelet-Derived Growth Factor Receptor ) c-Kit Met (Mesenchymal-Epithelial Transition Factor) Src p38 MAPKs (Mitogen-Activated Protein Kinases) ERK1/2 JNK (c-Jun N-Terminal Kinase, MAPK8) PKC (Protein Kinase C) CDKs (Cyclin-Dependent Kinases) Auroras Akt/PKB (Protein Kinase B) Phosphoinositide 3-Kinases Syk (Spleen Tyrosind Kinase) JAK (Janus Kinase) Kinase Inhibitors in Inflammation and Infectious Diseases DESIGN PRINCIPLES OF DEEP POCKET-TARGETING PROTEIN KINASE INHIBITORS Introduction Classification of Protein Kinase Inhibitors Type II Inhibitors Common Features of Type II Inhibitors Design Strategies for Type II Inhibitors Comparative Analysis of the Different Design Strategies Conclusions and Outlook FROM DISCOVERY TO CLINIC: AURORA KINASE INHIBITORS AS NOVEL TREATMENTS FOR CANCER Introduction Biological Roles of the Aurora Kinases Aurora Kinases and Cancer In Vitro Phenotype of Aurora Kinase Inhibitors Aurora Kinase Inhibitors X-Ray Crystal Structures of Aurora Kinases Summary PART III: Application of Kinase Inhibitors to Therapeutic Indication Areas DISCOVERY AND DESIGN OF PROTEIN KINASE INHIBITORS: TARGETING THE CELL CYCLE IN ONCOLOGY Protein Kinase Inhibitors in Anticancer Drug Development Structure-Guided Design of Small-Molecule Inhibitors of the Cyclin-Dependent Kinases Catalytic Site Inhibitors ATP Site Specificity Alternate Strategies for Inhibiting CDKs Cyclin Groove Inhibitors (CGI) Inhibition of CDK-Cyclin Association Recent Developments in the Discovery and the Development of Aurora Kinase Inhibitors Development of Aurora Kinase Inhibitors through Screening and Structure-Guided Design Aurora Kinase Inhibitors in Clinical Trials Progress in the Identification of Potent and Selective Polo-Like Kinase Inhibitors Development of Small-Molecule Inhibitors of PLK1 Kinase Activty Discovery of Benzthiazole PLK1 Inhibitors Recent Structural Studies of the PLK1 Kinase Domain Additional Small-Molecule PLK1 Inhibitors Reported The Polo-Box Domain Future Developments MEDICINAL CHEMISTRY APPROACHES FOR THE INHIBITION OF THE p38 MAPK PATHWAY Introduction p38 MAP Kinase Basics p38 Activity and Inhibition First-Generation Inhibitors Pyridinyl-Imidazole Inhibitor: SB203580 N-Substituted Imidazole Inhibitors N,N'-Diarylurea-Based Inhibitors: BIRB796 Structurally Diverse Clinical Candidates Medicinal Ch