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Protein Kinases as Drug Targets

Bert Klebl (Editor), Gerhard Müller (Editor), Michael Hamacher (Editor), Raimund Mannhold (Series Editor), Hugo Kubinyi (Series Editor), Gerd Folkers (Series Editor)
ISBN: 978-3-527-63349-4
396 pages
March 2011
Protein Kinases as Drug Targets (3527633499) cover image


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.
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Table of Contents

List of Contributors.


A Personal Foreword.

Part One Hit Finding and Profiling for Protein Kinases: Assay Development and Screening, Libraries.

1 In Vitro Characterization of Small-Molecule Kinase Inhibitors (Doris Hafenbradl, Matthias Baumann, and Lars Neumann).

1.1 Introduction.

1.2 Optimization of a Biochemical Kinase Assay.

1.3 Measuring the Binding Affinity and Residence Time of Unusual Kinase Inhibitors.

1.4 Addressing ADME Issues of Protein Kinase Inhibitors in Early Drug Discovery.


2 Screening for Kinase Inhibitors: From Biochemical to Cellular Assays (Jan Eickhoff and Axel Choidas).

2.1 Introduction.

2.2 Factors that Influence Cellular Efficacy of Kinase Inhibitors.

2.3 Assays for Measurement of Cellular Kinase Activity.

2.4 Outlook.


3 Dissecting Phosphorylation Networks: The Use of Analogue-Sensitive Kinases and More Specific Kinase Inhibitors as Tools (Matthias Rabiller, Jeffrey R. Simard and Daniel Rauh).

3.1 Introduction.

3.2 Chemical Genetics.

3.3 The Application of ASKA Technology in Molecular Biology.

3.4 Conclusions and Outlook.


Part Two Medicinal Chemistry.

4 Rational Drug Design of Kinase Inhibitors for Signal Transduction Therapy (György Kéri, László O´´rfi, and Gábor Németh).

4.1 The Concept of Rational Drug Design.

4.2 3D Structure-Based Drug Design.

4.3 Ligand-Based Drug Design.

4.4 Target Selection and Validation.

4.5 Personalized Therapy with Kinase Inhibitors.

4.6 The NCLTM Technology and Extended Pharmacophore Modeling (Prediction-Oriented QSAR).

4.7 Non-ATP Binding Site-Directed or Allosteric Kinase Inhibitors.

4.8 The Master Keys for Multiple Target Kinase Inhibitors.

4.9 Conclusions.


5 Kinase Inhibitors in Signal Transduction Therapy (György Kéri, László Örfi, and Gábor Németh).

5.1 VEGFR (Vascular Endothelial Growth Factor Receptor).

5.2 Flt3 (FMS-Like Tyrosine Kinase 3).

5.3 Bcr-Abl (Breakpoint Cluster Region–Abelson Murine Leukemia Viral Oncogene Homologue).

5.4 EGFR (Epidermal Growth Factor Receptor).

5.5 IGFR (Insulin-Like Growth Factor Receptor).

5.6 FGFR (Fibroblast Growth Factor Receptor).

5.7 PDGFR (Platelet-Derived Growth Factor Receptor).

5.8 c-Kit.

5.9 Met (Mesenchymal-Epithelial Transition Factor).

5.10 Src.

5.11 p38 MAPKs (Mitogen-Activated Protein Kinases).

5.12 ERK1/2.

5.13 JNK (c-Jun N-Terminal Kinase, MAPK8).

5.14 PKC (Protein Kinase C).

5.15 CDKs (Cyclin-Dependent Kinases).

5.16 Auroras.

5.17 Akt/PKB (Protein Kinase B).

5.18 Phosphoinositide 3-Kinases.

5.19 Syk (Spleen Tyrosine Kinase).

5.20 JAK (Janus Kinase).

5.21 Kinase Inhibitors in Inflammation and Infectious Diseases.


6 Design Principles of Deep Pocket-Targeting Protein Kinase Inhibitors (Alexander C. Backes, Gerhard Müller, and Peter C. Sennhenn).

6.1 Introduction.

6.2 Classification of Protein Kinase Inhibitors.

6.3 Type II Inhibitors.

6.4 Common Features of Type II Inhibitors.

6.5 Design Strategies for Type II Inhibitors.

6.6 Comparative Analysis of the Different Design Strategies.

6.7 Conclusions and Outlook.


7 From Discovery to Clinic: Aurora Kinase Inhibitors as Novel Treatments for Cancer (Nicola Heron).

7.1 Introduction.

7.2 Biological Roles of the Aurora Kinases.

7.3 Aurora Kinases and Cancer.

7.4 In Vitro Phenotype of Aurora Kinase Inhibitors.

7.5 Aurora Kinase Inhibitors.

7.6 X-Ray Crystal Structures of Aurora Kinases.

7.7 Summary.


Part Three Application of Kinase Inhibitors to Therapeutic Indication Areas.

8 Discovery and Design of Protein Kinase Inhibitors: Targeting the Cell cycle in Oncology (Mokdad Mezna, George Kontopidis, and Campbell McInnes).

8.1 Protein Kinase Inhibitors in Anticancer Drug Development.

8.2 Structure-Guided Design of Small-Molecule Inhibitors of the Cyclin-Dependent Kinases.

8.3 Catalytic Site Inhibitors.

8.4 ATP Site Specificity.

8.5 Alternate Strategies for Inhibiting CDKs.

8.6 Cyclin Groove Inhibitors (CGI).

8.7 Inhibition of CDK–Cyclin Association.

8.8 Recent Developments in the Discovery and the Development of Aurora Kinase Inhibitors.

8.9 Development of Aurora Kinase Inhibitors through Screening and Structure-Guided Design.

8.10 Aurora Kinase Inhibitors in Clinical Trials.

8.11 Progress in the Identification of Potent and Selective Polo-Like Kinase Inhibitors.

8.12 Development of Small-Molecule Inhibitors of PLK1 Kinase Activity.

8.13 Discovery of Benzthiazole PLK1 Inhibitors.

8.14 Recent Structural Studies of the Plk1 Kinase Domain.

8.15 Additional Small-Molecule PLK1 Inhibitors Reported.

8.16 The Polo-Box Domain.

8.17 Future Developments.


9 Medicinal Chemistry Approaches for the Inhibition of the p38 MAPK Pathway (Stefan Laufer L, Simona Margutti, Dowinik Hauser).

9.1 Introduction.

9.2 p38 MAP Kinase Basics.

9.3 p38 Activity and Inhibition.

9.4 First-Generation Inhibitors.

9.5 Pyridinyl-Imidazole Inhibitor: SB203580.

9.6 N-Substituted Imidazole Inhibitors.

9.7 N,N0-Diarylurea-Based Inhibitors: BIRB796.

9.8 Structurally Diverse Clinical Candidates.

9.9 Medicinal Chemistry Approach on VX-745-Like Compounds.

9.10 Conclusion and Perspective for the Future.


10 Cellular Protein Kinases as Antiviral Targets (Luis M. Schang).

10.1 Introduction.

10.2 Antiviral Activities of the Pharmacological Cyclin-Dependent Kinase Inhibitors.

10.3 Antiviral Activities of Inhibitors of Other Cellular Protein Kinases.

10.4 Conclusion.


11 Prospects for TB Therapeutics Targeting Mycobacterium tuberculosis Phosphosignaling Networks (Yossef Av-Gay and Tom Alber).

11.1 Introduction.

11.2 Rationale for Ser/Thr Protein Kinases and Protein Phosphatases as Drug Targets.

11.3 Drug Target Validation by Genetic Inactivation.

11.4 STPK Mechanisms, Substrates, and Functions.

11.5 M. tuberculosis STPK Inhibitors.

11.6 Conclusions and Prospects.



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Author Information

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.

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"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)


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