Edited by Bert Klebl, Gerhard Müller, and Michael Hamacher. Protein Kinases as Drug Targets WILEY VCH. WILEY-VCH Verlag GmbH & Co.

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1 Edited by Bert Klebl, Gerhard Müller, and Michael Hamacher Protein Kinases as Drug Targets ~ WILEY VCH WILEY-VCH Verlag GmbH & Co. KGaA

2 Contents List of Contributors Preface XV A Personal Foreword XI XVI I Part One Hit Finding and Profiling for Protein Kinases: Assay Development and Screening, Libraries 1 In Vitro Characterization ofsmall-molecule Kinase Inhibitors 3 Doris Hafenbradl, Matthias Baumann, and Lars Neumann 1.1 Introduction Optimization of a Biochemical Kinase Assay Step 1: Identification of a Substrate and Controlling of the Linearity between Signal and Kinase Concentration Step 2: Assay Wall and Optimization of the Reaction Buffer Step 3: The Michaelis-Menten Constant Km and the ATP Concentration Step 4: Signal Linearity throughout the Reaction Time and Dependence on the Kinase Concentration Step 5: Assay Validation by Measurement of the ICso of Reference Inhibitors Measuring the Binding Affinity and Residence Time ofunusual Kinase Inhibitors Washout Experiments Surface Plasmon Resonance Classical Methods with Fluorescent Probes Preincubation oftarget and Inhibitor Reporter Displacement Assay Implications for Dmg Discovery Addressing ADME Issues of Protein Kinase Inhibitors in Early Dmg Discovery 26 Protein Kinases as Drug Targets. Edited by B. Kleb!, G. Müller. and M. Hamacher Copyright 2011 WILEY-VCH Verlag GmbH & Co. KGaA. Weinheim ISBN:

3 VII Contents Introduction 26 Experimental Approaches to Drug Absorption 30 Measuring Solubility 30 Measuring Lipophilicity and Ionization 30 Measuring Permeability 31 Transporter Assays Addressing P-gp Interaction 33 Experimental Approaches to Drug Metabolism 34 Background and Concepts 34 Measuring Metabolie Stability 37 Measuring CYP450 Inhibition 39 References 39 Screening for Kinase Inhibitors: From Biochemical to Cellular Assays 45 Jan Eickhoff and Axel Choidas Introduction 45 Kinase Inhibitors for Disseetion of Signaling Pathways 46 Cellular Kinase Assays for Drug Discovery Applications 46 Factors that Influence Cellular Efficacy of Kinase Inhibitors 47 Competition from ATP 47 Substrate Phosphorylation Levels 51 Ultrasensitivity of Kinase Signaling Cascades 51 Cell Permeability 52 Cellular Kinase Concentrations 53 Effects of Inhibitors Not Related to Substrate Phosphorylation 54 Assays for Measurement of Cellular Kinase Activity 55 Antibody-Based Detection 56 High-Content Screening 59 Use of Genetically Engineered Cell Lines 60 Genetically Encoded Biosensors 61 Label-Free Technologies 62 Analysis of Kinase Family Selectivity 62 SILAC 62 Affinity Chromatography with Immobilized Kinase Inhibitors 63 Outlook 63 References 64 3 Dissecting Phosphorylation Networks: The Use of Analogue-Sensitive Kinases and More Specific Kinase Inhibitors as Tools 69 Matthias Rabi/ler, Jeffrey R. Simard and Daniel Rauh 3.1 Introduction Chemical Genetics Engineering ASKA Ligand-Kinase Pairs The Application of ASKA Technology in Molecular Biology Identification ofkinase Substrates 76

4 Contents I VII Studies on Kinase Inhibition Alternative Approaches to Specifically Targeting Kinases of Interest Conclusions and Outlook 80 References 81 Part Two Medicinal Chemistry 85 4 Rational Drug Design of Kinase Inhibitors for Signal Transduction Therapy 87 György Keri, Lasz/6 OrJi, and Gabor Nemeth 4.1 The Concept of Rational Drug Design D Structure-Based Drug Design Ligand-Based Drug Design Active Analogue Approach D Quantitative Structure-Activity Relationships Target Selection and Validation Personalized Therapy with Kinase Inhibitors Target Fishing: Kinase Inhibitor-Based Affinity Chromatography The NCL 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 Application of KinaTo?M for the Second-Generation Kinase Inhibitors Conclusions 107 References Kinase Inhibitors in Signal Transduction Therapy 115 György Keri, Lasz/6 OrJi, and Gabor Nemeth 5.1 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 (Fibroblast Growth Factor Receptor) PDGFR (Platelet-Derived Growth Factor Receptor) c-kit Met (Mesenchymal-Epithelial Transition Factor) Src p38 MAPKs (Mitogen-Activated Protein Kinases) ERK1/ JNK (c-jun N-Terminal Kinase, MAPK8) PKC (Protein Kinase C) CDKs (Cyclin-Dependent Kinases) 127

5 VIII \ Contents Auroras 127 AktjPKB (Protein Kinase B) 129 Phosphoinositide 3-Kinases 129 Syk (Spleen Tyrosine Kinase) 130 JAK (Janus Kinase) 130 Kinase Inhibitors in Inflammation and Infectious Diseases 131 Inflammation 131 Infection 132 References 134 Design Principles ofdeep Pocket-Targeting Protein Kinase Inhibitors 145 Alexander C. Backes, Gerhard Müller, and Peter C. Sennhenn Introduction 145 Classification of Protein Kinase Inhibitors 147 Type II Inhibitors 150 Common Features oftype II Inhibitors 154 Design Strategies for Type II Inhibitors 155 F2B Approach 160 B2F Approach 166 B2B Approach 169 Hybrid (F2B + B2F) Approach 173 Comparative Analysis of the Different Design Strategies 180 Conclusions and Outlook 187 References 190 From Discovery to Clinic: Aurora Kinase Inhibitors as Novel Treatments for Cancer 195 Nicola Heron Introduction 195 Biological Roles of the Aurora Kinases 195 Aurora Kinases and Cancer 196 In Vitro Phenotype of Aurora Kinase Inhibitors 197 Aurora Kinase Inhibitors 203 The Discovery of AZD Anilinoquinazolines: ZM Next-Generation Quinazolines: Heterocyclic Analogues 204 Amino-Thiazolo and Pyrazolo Acetanilide Quinazolines 208 MK-0457 (VX-680) 214 PHA MLN AT X-Ray Crystal Structures of Aurora Kinases 221 Summary 221 References 222

6 Contents IIX Part Three Application of Kinase Inhibitors to Therapeutic Indication Areas Discovery and Design ofprotein Kinase Inhibitors: Targeting the Cell cycle in Oncology 231 Mokdad Mezna, George Kontopidis, and CampbelJ Mclnnes 8.1 Protein Kinase Inhibitors in Anticancer Drug Development Structure-Guided Design of Small-Molecule Inhibitors ofthe 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 Activity Discovery of Benzthiazole PLK1 Inhibitors Recent Structural Studies of the Plkl Kinase Domain Additional Small-Molecule PLK1 Inhibitors Reported The Polo-Box Domain Future Developments 259 References Medicinal Chemistry Approaches for the Inhibition ofthe p38 MAPK Pathway 271 Stefan Laufer L, Simona Margutti, Dowinik Hauser 9.1 Introduction p38 MAP Kinase Basics p38 Activity and Inhibition First-Generation Inhibitors Pyridinyl-Imidazole Inhibitor: SB N-Substituted Imidazole Inhibitors N,N'-Diarylurea-Based Inhibitors: BIRB Structurally Diverse Clinical Candidates Medicinal Chemistry Approach on VX-745-Like Compounds Conclusion and Perspective for the Future 301 References 302

7 xl Contents Cellular Protein Kinases as Antiviral Targets 305 Luis M. Schang Introduction 305 Antiviral Activities of the Pharmacological Cyclin-Dependent Kinase Inhibitors 310 Relevant Properties of CDKs and PCIs 310 Antiviral Activities of PCIs 327 Antiviral Activities of PCls against Herpesviruses 327 Antiviral Activities of PCls against HIV 332 Antiviral Activities of PCIs against Other Viruses 335 PCls Can be Used in Combination Therapies 336 PCIs Inhibit Viral Pathogenesis 337 Antiviral Activities of Inhibitors of Other Cellular Protein Kinases 338 Conclusion 339 References 341 Prospects for TB Therapeutics Targeting Mycobacterium tuberculosis Phosphosignaling Networks 349 Yossef Av-Gay and Tom Alber Introduction 349 Rationale for Ser/Thr Protein Kinases and Protein Phosphatases as Drug Targets 350 Drug Target Validation by Genetic Inactivation 351 STPK Mechanisms, Substrates, and Functions 352 M. tuberculosis STPK Inhibitors 355 Conclusions and Prospects 359 References 359 Index 365

Protein Kinases as Drug Targets

Methods and Principles in Medicinal Chemistry 49 Protein Kinases as Drug Targets Bearbeitet von Bert Klebl, Gerhard Müller, Michael Hamacher, Raimund Mannhold, Hugo Kubinyi, Gerd Folkers 1st Edition 2011