Protein Kinases as Drug Targets

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