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E-grāmata: Protein Kinases as Drug Targets

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With Kinase inhibitors being widely seen as the long-sought 'magic bullet' to conquer cancer, this fully comprehensive guide to kinase inhibitor drug development covers the entire drug pipeline from target identification to compound development and clinical application.


Volume 1 focuses upon the medicinal chemistry of kinase drugs, from target identification to lead optimization, and contains numerous contributions from large and small pharmaceutical companies.

Volume 2 surveys current and future therapeutic application areas for kinase inhibitor drugs, with a strong focus on oncology drugs, as this is the most important therapeutic field for these drugs. In addition, all six currently approved kinase inhibitor drugs (small molecules and antibodies) are described, and their performances in clinical practice are discussed.

Recenzijas

"In summary, Protein Kinases as Drug Targets is an excellent book that can be highly recommended to both experts and novices in the various disciplines in this field of research; lecturers searching for comprehensive drug discovery stories will also be happy to find numerous instructive examples." (ChemMedChem, 1 December 2011)

List of Contributors
xi
Preface xv
A Personal Foreword xviii
Part One Hit Finding and Profiling for Protein Kinases: Assay Development and Screening, Libraries
1(84)
1 In Vitro Characterization of Small-Molecule Kinase Inhibitors
3(42)
Doris Hafenbradl
Matthias Baumann
Lars Neumann
1.1 Introduction
3(1)
1.2 Optimization of a Biochemical Kinase Assay
4(11)
1.2.1 Step 1: Identification of a Substrate and Controlling of the Linearity between Signal and Kinase Concentration
4(2)
1.2.2 Step 2: Assay Wall and Optimization of the Reaction Buffer
6(4)
1.2.3 Step 3: The Michaelis--Menten Constant Km and the ATP Concentration
10(2)
1.2.4 Step 4: Signal Linearity throughout the Reaction Time and Dependence on the Kinase Concentration
12(3)
1.2.5 Step 5: Assay Validation by Measurement of the IC50 of Reference Inhibitors
15(1)
1.3 Measuring the Binding Affinity and Residence Time of Unusual Kinase Inhibitors
15(11)
1.3.1 Washout Experiments
18(1)
1.3.2 Surface Plasmon Resonance
19(2)
1.3.3 Classical Methods with Fluorescent Probes
21(1)
1.3.4 Preincubation of Target and Inhibitor
22(1)
1.3.5 Reporter Displacement Assay
22(3)
1.3.6 Implications for Drug Discovery
25(1)
1.4 Addressing ADME Issues of Protein Kinase Inhibitors in Early Drug Discovery
26(19)
1.4.1 Introduction
26(4)
1.4.2 Experimental Approaches to Drug Absorption
30(1)
1.4.2.1 Measuring Solubility
30(1)
1.4.2.2 Measuring Lipophilicity and Ionization
30(1)
1.4.2.3 Measuring Permeability
31(2)
1.4.2.4 Transporter Assays Addressing P-gp Interaction
33(1)
1.4.3 Experimental Approaches to Drug Metabolism
34(1)
1.4.3.1 Background and Concepts
34(3)
1.4.3.2 Measuring Metabolic Stability
37(2)
1.4.3.3 Measuring CYP450 Inhibition
39(1)
References
39(6)
2 Screening for Kinase Inhibitors: From Biochemical to Cellular Assays
45(24)
Jan Eickhoff
Axel Choidas
2.1 Introduction
45(2)
2.1.1 Kinase Inhibitors for Dissection of Signaling Pathways
46(1)
2.1.2 Cellular Kinase Assays for Drug Discovery Applications
46(1)
2.2 Factors that Influence Cellular Efficacy of Kinase Inhibitors
47(8)
2.2.1 Competition from ATP
47(4)
2.2.2 Substrate Phosphorylation Levels
51(1)
2.2.3 Ultrasensitivity of Kinase Signaling Cascades
51(1)
2.2.4 Cell Permeability
52(1)
2.2.5 Cellular Kinase Concentrations
53(1)
2.2.6 Effects of Inhibitors Not Related to Substrate Phosphorylation
54(1)
2.3 Assays for Measurement of Cellular Kinase Activity
55(8)
2.3.1 Antibody-Based Detection
56(3)
2.3.2 High-Content Screening
59(1)
2.3.3 Use of Genetically Engineered Cell Lines
60(1)
2.3.4 Genetically Encoded Biosensors
61(1)
2.3.5 Label-Free Technologies
62(1)
2.3.6 Analysis of Kinase Family Selectivity
62(1)
2.3.7 SILAC
62(1)
2.3.8 Affinity Chromatography with Immobilized Kinase Inhibitors
63(1)
2.4 Outlook
63(6)
References
64(5)
3 Dissecting Phosphorylation Networks: The Use of Analogue-Sensitive Kinases and More Specific Kinase Inhibitors as Tools
69(16)
Matthias Rabiller
Jeffrey R. Simard
Daniel Rauh
3.1 Introduction
69(2)
3.2 Chemical Genetics
71(5)
3.2.1 Engineering ASKA Ligand-Kinase Pairs
71(5)
3.3 The Application of ASKA Technology in Molecular Biology
76(4)
3.3.1 Identification of Kinase Substrates
76(1)
3.3.2 Studies on Kinase Inhibition
76(2)
3.3.3 Alternative Approaches to Specifically Targeting Kinases of Interest
78(2)
3.4 Conclusions and Outlook
80(5)
References
81(4)
Part Two Medicinal Chemistry
85(144)
4 Rational Drug Design of Kinase Inhibitors for Signal Transduction Therapy
87(28)
Gyorgy Keri
Laszlo Orfi
Cabor Nemeth
4.1 The Concept of Rational Drug Design
88(1)
4.2 3D Structure-Based Drug Design
89(3)
4.3 Ligand-Based Drug Design
92(1)
4.3.1 Active Analogue Approach
92(1)
4.3.2 3D Quantitative Structure-Activity Relationships
92(1)
4.4 Target Selection and Validation
93(3)
4.5 Personalized Therapy with Kinase Inhibitors
96(3)
4.5.1 Target Fishing: Kinase Inhibitor-Based Affinity Chromatography
97(2)
4.6 The NCL™ Technology and Extended Pharmacophore Modeling (Prediction-Oriented QSAR)
99(2)
4.7 Non-ATP Binding Site-Directed or Allosteric Kinase Inhibitors
101(1)
4.8 The Master Keys for Multiple Target Kinase Inhibitors
102(5)
4.8.1 Application of KinaTor™ for the Second-Generation Kinase Inhibitors
105(2)
4.9 Conclusions
107(8)
References
109(6)
5 Kinase Inhibitors in Signal Transduction Therapy
115(30)
Gyorgy Keri
Laszlo Orfi
Cabor Nemeth
5.1 VEGFR (Vascular Endothelial Growth Factor Receptor)
115(1)
5.2 Flt3 (FMS-Like Tyrosine Kinase 3)
116(2)
5.3 Ber-Abl (Breakpoint Cluster Region-Abelson Murine Leukemia Viral Oncogene Homologue)
118(1)
5.4 EGFR (Epidermal Growth Factor Receptor)
118(2)
5.5 IGFR (Insulin-like Growth Factor Receptor)
120(1)
5.6 FGFR (Fibroblast Growth Factor Receptor)
120(1)
5.7 PDGFR (Platelet-Derived Growth Factor Receptor)
121(1)
5.8 c-Kit
121(1)
5.9 Met (Mesenchymal-Epithelial Transition Factor)
122(1)
5.10 Src
123(1)
5.11 p38 MAPKs (Mitogen-Activated Protein Kinases)
123(1)
5.12 ERK1/2
124(2)
5.13 JNK (c-Jun N-Termmal Kinase. MAPK8)
126(1)
5.14 PKC (Protein Kinase C)
126(1)
5.15 CDKs (Cyclin-Dependent Kinases)
127(1)
5.16 Auroras
127(2)
5.17 Akt/PKB (Protein Kinase B)
129(1)
5.18 Phosphoinositide 3-Kinases
129(1)
5.19 Syk (Spleen Tyrosine Kinase)
130(1)
5.20 JAK (Janus Kinase)
130(1)
5.21 Kinase Inhibitors in Inflammation and Infectious Diseases
131(14)
5.21.1 Inflammation
131(1)
5.21.2 Infection
132(2)
References
134(11)
6 Design Principles of Deep Pocket-Targeting Protein Kinase Inhibitors
145(50)
Alexander C. Backes
Gerhard Muller
Peter C. Sennhenn
6.1 Introduction
145(2)
6.2 Classification of Protein Kinase Inhibitors
147(3)
6.3 Type II Inhibitors
150(4)
6.4 Common Features of Type II Inhibitors
154(1)
6.5 Design Strategies for Type II Inhibitors
155(25)
6.5.1 F2B Approach
160(6)
6.5.2 B2F Approach
166(3)
6.5.3 B2B Approach
169(4)
6.5.4 Hybrid (F2B + B2F) Approach
173(7)
6.6 Comparative Analysis of the Different Design Strategies
180(7)
6.7 Conclusions and Outlook
187(8)
References
190(5)
7 From Discovery to Clinic: Aurora Kinase Inhibitors as Novel Treatments for Cancer
195(34)
Nicola Heron
7.1 Introduction
195(1)
7.2 Biological Roles of the Aurora Kinases
195(1)
7.3 Aurora Kinases and Cancer
196(1)
7.4 In Vitro Phenotype of Aurora Kinase Inhibitors
197(6)
7.5 Aurora Kinase Inhibitors
203(18)
7.5.1 The Discovery of AZD1152
203(1)
7.5.1.1 Anilinoquinazolines: ZM447439
203(1)
7.5.1.2 Next-Generation Quinazolines: Heterocyclic Analogues
204(4)
7.5.1.3 Amino-Thiazolo and Pyrazolo Acetanilide Quinazolines
208(6)
7.5.2 MK-0457 (VX-680)
214(1)
7.5.3 PHA-739358
215(4)
7.5.4 MLN8054
219(1)
7.5.5 AT9283
220(1)
7.6 X-Ray Crystal Structures of Aurora Kinases
221(1)
7.7 Summary
221(8)
References
222(7)
Part Three Application of Kinase Inhibitors to Therapeutic Indication Areas
229(136)
8 Discovery and Design of Protein Kinase Inhibitors: Targeting the Cell cycle in Oncology
231(41)
Mokdad Mezna
George Kontopidis
Campbell McInnes
8.1 Protein Kinase Inhibitors in Anticancer Drug Development
231(2)
8.2 Structure-Guided Design of Small-Molecule Inhibitors of the Cyclin-Dependent Kinases
233(1)
8.3 Catalytic Site Inhibitors
234(2)
8.4 ATP Site Specificity
236(3)
8.5 Alternate Strategies for Inhibiting CDKs
239(1)
8.6 Cyclin Groove Inhibitors (CGI)
240(2)
8.7 Inhibition of CDK-Cyclin Association
242(1)
8.8 Recent Developments in the Discovery and the Development of Aurora Kinase Inhibitors
242(2)
8.9 Development of Aurora Kinase Inhibitors through Screening and Structure-Guided Design
244(4)
8.10 Aurora Kinase Inhibitors in Clinical Trials
248(2)
8.11 Progress in the Identification of Potent and Selective Polo-Like Kinase Inhibitors
250(2)
8.12 Development of Small-Molecule Inhibitors of PLK1 Kinase Activity
252(2)
8.13 Discovery of Benzthiazole PLK1 Inhibitors
254(1)
8.14 Recent Structural Studies of the Plk1 Kinase Domain
255(1)
8.15 Additional Small-Molecule PLK1 Inhibitors Reported
256(1)
8.16 The Polo-Box Domain
257(2)
8.17 Future Developments
259(13)
References
259(13)
9 Medicinal Chemistry Approaches for the Inhibition of the p38 MAPK Pathway
272(33)
Stefan Laufer L. Simona Margutti
Dowinik Hauser
9.1 Introduction
271(1)
9.2 p38 MAP Kinase Basics
271(4)
9.3 p38 Activity and Inhibition
275(3)
9.4 First-Generation Inhibitors
278(1)
9.5 Pyridinyl-Imidazole Inhibitor: SB203580
278(4)
9.6 N-Substituted Imidazole Inhibitors
282(4)
9.7 N, N'-Diarylurea-Based Inhibitors: BIRB796
286(2)
9.8 Structurally Diverse Clinical Candidates
288(9)
9.9 Medicinal Chemistry Approach on VX-745-Like Compounds
297(4)
9.10 Conclusion and Perspective for the Future
301(4)
References
302(3)
10 Cellular Protein Kinases as Antiviral Targets
305(44)
Luis M. Schang
10.1 Introduction
305(5)
10.2 Antiviral Activities of the Pharmacological Cyclin-Dependent Kinase Inhibitors
310(28)
10.2.1 Relevant Properties of CDKs and PCIs
310(17)
10.2.2 Antiviral Activities of PCIs
327(1)
10.2.2.1 Antiviral Activities of PCIs against Herpesviruses
327(5)
10.2.2.2 Antiviral Activities of PCIs against HIV
332(3)
10.2.2.3 Antiviral Activities of PCIs against Other Viruses
335(1)
10.2.3 PCIs Can be Used in Combination Therapies
336(1)
10.2.4 PCIs Inhibit Viral Pathogenesis
337(1)
10.3 Antiviral Activities of Inhibitors of Other Cellular Protein Kinases
338(1)
10.4 Conclusion
339(10)
References
341(8)
11 Prospects for TB Therapeutics Targeting Mycobacterium tuberculosis Phosphosignaling Networks
349(16)
Yossef Av-Gay
Tom Alber
11.1 Introduction
349(1)
11.2 Rationale for Ser/Thr Protein Kinases and Protein Phosphatases as Drug Targets
350(1)
11.3 Drug Target Validation by Genetic Inactivation
351(1)
11.4 STPK Mechanisms, Substrates, and Functions
352(3)
11.5 M. tuberculosis STPK Inhibitors
355(4)
11.6 Conclusions and Prospects
359(6)
References
359(6)
Index 365
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 Montreal, Canada. Gerhard Muller 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-Universitat in Dusseldorf, Germany. Subsequent to his PhD, he joined the Medizinisches Proteom-Center, Ruhr-Universitat 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.
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