Protein Kinases as Drug Targets E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Serie: Methods and Principles in Medicinal Chemistry
• Sprache: Englisch

Seitenzahl: 728

Veröffentlichungsjahr: 2011

Beschreibung

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.

Leseprobe

Contents

Cover

Methods and Principles in Medicinal Chemistry

Title Page

Copyright

List of Contributors

Preface

A Personal Foreword

References

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

Chapter 1: In Vitro Characterization of Small-Molecule Kinase Inhibitors

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

Acknowledgment

References

Chapter 2: Screening for Kinase Inhibitors: From Biochemical to Cellular Assays

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

References

Chapter 3: Dissecting Phosphorylation Networks: The Use of Analogue-Sensitive Kinases and More Specific Kinase Inhibitors as Tools

3.1 Introduction

3.2 Chemical Genetics

3.3 The Application of ASKA Technology in Molecular Biology

3.4 Conclusions and Outlook

References

Part Two: Medicinal Chemistry

Chapter 4: Rational Drug Design of Kinase Inhibitors for Signal Transduction Therapy

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 NCL™ 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

References

Chapter 5: Kinase Inhibitors in Signal Transduction Therapy

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

References

Chapter 6: Design Principles of Deep Pocket-Targeting Protein Kinase Inhibitors

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

6.8 Abbreviations

Acknowledgments

References

Chapter 7: From Discovery to Clinic: Aurora Kinase Inhibitors as Novel Treatments for Cancer

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

References

Part Three: Application of Kinase Inhibitors to Therapeutic Indication Areas

Chapter 8: Discovery and Design of Protein Kinase Inhibitors: Targeting the Cell cycle in Oncology

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

References

Chapter 9: Medicinal Chemistry Approaches for the Inhibition of the p38 MAPK Pathway

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,N′-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

Acknowledgments

References

Chapter 10: Cellular Protein Kinases as Antiviral Targets

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

Acknowledgments

References

Chapter 11: Prospects for TB Therapeutics Targeting Mycobacterium tuberculosis Phosphosignaling Networks

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

Acknowledgments

References

Index

Methods and Principles in Medicinal Chemistry

Edited by R. Mannhold, H. Kubinyi, G. Folkers

Editorial Board

H. Buschmann, H. Timmerman, H. van de Waterbeemd, T. Wieland

Previous Volumes of this Series:

Sotriffer, Christopher (Ed.)

Virtual Screening

Principles, Challenges, and Practical

Guidelines

2011

ISBN: 978-3-527-32636-5

Vol. 48

Rautio, Jarkko (Ed.)

Prodrugs and Targeted Delivery

Towards Better ADME Properties

2011

ISBN: 978-3-527-32603-7

Vol. 47

Smit, Martine J. / Lira, Sergio A. / Leurs,

Rob (Eds.)

Chemokine Receptors as

Drug Targets

2011

ISBN: 978-3-527-32118-6

Vol. 46

Ghosh, Arun K. (Ed.)

Aspartic Acid Proteases as

Therapeutic Targets

2010

ISBN: 978-3-527-31811-7

Vol. 45

Ecker, Gerhard F. / Chiba, Peter (Eds.)

Transporters as Drug Carriers

Structure, Function, Substrates

2009

ISBN: 978-3-527-31661-8

Vol. 44

Faller, Bernhard / Urban, Laszlo (Eds.)

Hit and Lead Profiling

Identification and Optimization

of Drug-like Molecules

2009

ISBN: 978-3-527-32331-9

Vol. 43

Sippl, Wolfgang / Jung, Manfred (Eds.)

Epigenetic Targets in Drug

Discovery

2009

ISBN: 978-3-527-32355-5

Vol. 42

Todeschini, Roberto / Consonni, Viviana

Molecular Descriptors for

Chemoinformatics

Volume I: Alphabetical Listing /

Volume II: Appendices, References

2009

ISBN: 978-3-527-31852-0

Vol. 41

van de Waterbeemd, Han / Testa,

Bernard (Eds.)

Drug Bioavailability

Estimation of Solubility, Permeability,

Absorption and Bioavailability

Second, Completely Revised Edition

2008

ISBN: 978-3-527-32051-6

Vol. 40

Ottow, Eckhard/Weinmann, Hilmar (Eds.)

Nuclear Receptors as Drug

Targets

2008

ISBN: 978-3-527-31872-8

Vol. 39

Series Editors

Prof. Dr. Raimund Mannhold

Molecular Drug Research Group

Heinrich-Heine-Universität

Universitätsstrasse 1

40225 Düsseldorf

Germany

[email protected]

Prof. Dr. Hugo Kubinyi

Donnersbergstrasse 9

67256 Weisenheim am Sand

Germany

[email protected]

Prof. Dr. Gerd Folkers

Collegium Helveticum

STW/ETH Zurich

8092 Zurich

Switzerland

[email protected]

Volume Editors

Dr. Bert Klebl

Lead Discovery Center GmbH

Emil-Figge-Straße 76 a

44227 Dortmund

Germany

Dr. Gerhard Müller

Proteros Fragements GmbH

Am Klopferspitz 19

82152 Planegg

Germany

Dr. Michael Hamacher

Lead Discovery Center GmbH

Emil-Figge-Str. 76 a

44227 Dortmund

Germany

Cover Description

ATP binding site of the Cyclin-dependent protein kinase 7 (CDK7), a member of the CDK family involved in the regulation of the cell cycle and transcription. The kinase active site is divided in sub-sites according to its interactions, varying between individual enzymes and allowing the indiviual design of selective inhibitors. (Photo courtesy C. McInnes)

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

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The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at http://dnb.d-nb.de.

© 2011 Wiley-VCH Verlag & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany

All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.

ISBN: 978-3-527-31790-5

List of Contributors

Tom Alber

University of California

Department of Molecular and Cell

Biology

374B Stanley Hall #3220

Berkeley, CA 94720-3220

USA

Yossef Av-Gay

University of British Columbia

Department of Medicine

Division of Infectious Diseases

Vancouver, British Columbia

Canada V5Z 3J5

Alexander C. Backes

Sandoz GmbH

Sandoz Development Center

Biochemiestrasse 10

6336 Langkampfen

Austria

Matthias Baumann

Lead Discovery Center GmbH

Emil-Figge-Str 76a

44227 Dortmund

Germany

Axel Choidas

Lead-Discovery Center GmbH

Emil-Figge-Straße 76a

44227 Dortmund

Germany

Jan Eickhoff

Lead-Discovery Center GmbH

Emil-Figge-Straße 76a

44227 Dortmund

Germany

Doris Hafenbradl

BioFocus AG

Gewerbestrasse 16

4123 Allschwil

Switzerland

Nicola Heron

Devices for Dignity

Sheffield Teaching Hospitals NMS

Foundation Trust

Royal Hallamshire Hospital

Glossop Road Sheffield, S10 2YF

UK

György Kéri

Vichem Chemie Research Ltd.

Herman Ottó u. 15

1022 Budapest

Hungary

and

Semmelweis University

Hungarian Academy of Sciences

Pathobiochemical Research Group

Tüzoltó u. 37-47

1094 Budapest

Hungary

George Kontopidis

University of Thessaly

Veterinary School

Department of Biochemistry

43100 Karditsa

Greece

Stefan Laufer

Eberhard-Karls-Universität Tübingen

Pharmazeutisches Institut

Auf der Morgenstelle 8

72076 Tübingen

Germany

Campbell McInnes

South Carolina College of Pharmacy

715 Sumter St.

Columbia, SC 29208

USA

Mokdad Mezna

Beatson Institute for Cancer Research

Translational Research

Garscube Estateswitchback Road

Glasgow G61 1BD

UK

Gerhard Müller

Proteros Fragments GmbH

Fraunhoferstr. 20

82152 Martinsried

Germany

Góbor Németh

Vichem Chemie Research Ltd.

Herman Ottó u. 15

1022 Budapest

Hungary

Lars Neumann

Proteros Biostructures

Am Klopferspitz 19

82152 Martinsried

Germany

Lószló Orfi

Vichem Chemie Research Ltd.

Herman Ottó u. 15

1022 Budapest

Hungary

and

Semmelweis University

Department of Pharmaceutical

Chemistry

Hogyes Endre u. 9

1092 Budapest

Hungary

Matthias Rabiller

Chemical Genomics Centre of the

Max Planck Society

Otto-Hahn-Str. 15

44227 Dortmund

Germany

Daniel Rauh

Chemical Genomics Centre of the

Max Planck Society

Otto-Hahn-Str. 15

44227 Dortmund

Germany

Luis M. Schang

University of Alberta

Department of Biochemistry

327 Heritage Medical Research Center

Edmonton, Alberta

Canada, T6G 2S2

Peter C. Sennhenn

Proteros Fragments GmbH

Fraunhoferstr. 20

82152 Martinsried

Germany

Jeffrey R. Simard

Chemical Genomics Centre of the

Max Planck Society

Otto-Hahn-Str. 15

44227 Dortmund

Germany

Preface

Protein kinases are a huge group of evolutionary and structurally related enzymes, which by phosphorylation of certain amino acids, in first-line serine/threonine and tyrosine, activate a multitude of proteins. In this manner, they mediate signal transduction in cell growth and differentiation. The therapeutic potential of kinase inhibitors results from the crucial role kinases (as well as some kinase mutants and hybrids resulting from chromosomal translocation) play in tumor progression and in several other diseases. With a group size of more than 500 individual members, the “kinome,” that is, the sum of all kinase genes, constitutes about 2% of the human genome. Since the isolation of the first Ser/Thr-specific kinase in the muscle in 1959, it took another 20 years until tyrosine protein kinases were discovered and another 20 years before the first 3D structure of a kinase was determined. Starting with the 3D structure of protein kinase A in 1991, many more structures were elucidated in the meantime, in their active and inactive forms, without and with ligands other than ATP. These structures show not only the close structural relationship between all kinases but also the high complexity of their allosteric regulation. Today, the term “protein kinase” retrieves almost 2000 entries from the Protein Data Bank of 3D structures; most of these structures are protein–ligand complexes with about 1000 different ligands. All kinases show a highly conserved binding site for ATP, and for this reason they were for long time considered nondruggable targets. This view was supported by the fact that the natural product staurosporine inhibits a huge number of kinases in a nonspecific manner. Still today, staurosporine is the most promiscuous kinase inhibitor, despite its large size. However, with increase in structural knowledge, additional pockets were discovered in direct vicinity of the binding motif of the adenine part of ATP (the “hinge region”). Step by step, these pockets were explored and kinase inhibitors of higher specificity emerged. Finally, the optimization of a PKC inhibitor to the bcr/abl tyrosine kinase inhibitor imatinib (Gleevec®, Novartis) marked a breakthrough in specific tumor therapy. Although initially designed for the treatment of chronic myelogenous leukemia, the drug turned out to be beneficial also for the treatment of gastrointestinal stromal tumors (GISTs). Several other kinase inhibitors followed, with significantly different specificity profiles. Even nonspecific inhibitors, such as sunitinib (Sutent®, Pfizer), are valuable anticancer drugs, in this case for the therapy of advanced kidney cancer and as the second-line treatment of GIST, in cases where Gleevec® fails. Due to the multitude of tumor forms, resulting from various mechanisms, research on kinase inhibitors is now one of the hottest topics in pharmaceutical industry. Resistance to some kinase inhibitors forces the industry to also search for analogues with a broader spectrum of inhibitory activity. As of today, nine small-molecule kinase inhibitors for the treatment of oncological diseases have reached the market and many more are in different phases of clinical development. Even the first kinase inhibitors targeted toward nononcological applications, such as inflammatory disease states, have reached late-stage clinical development.

We are very grateful to Bert Klebl, Gerhard Müller, and Michael Hamacher who assembled a team of leading scientists for discussion of various topics of protein kinase inhibitors, including assay development, hit finding and profiling, medicinal chemistry, and application of kinase inhibitors to various therapeutic areas. We are also very grateful to all chapter authors who contributed their manuscripts on time. Of course, we appreciate the ongoing support of Frank Weinreich and Nicola Oberbeckmann-Winter, Wiley-VCH, for our book series “Methods and Principles in Medicinal Chemistry” and their valuable collaboration in this project.

September 2010

Raimund Mannhold, DüsseldorfHugo Kubinyi, Weisenheim am SandGerd Folkers, Zürich

A Personal Foreword

Kinase inhibitors are one of the fastest emerging fields in pharmaceutical research, reigning at “No. 2” in terms of overall spending for discovery and development of pharmaceuticals, when split according to target family classes. In our own professional histories, we still witnessed the dogma in pharmaceutical industry claiming that protein kinases are considered to be nondruggable targets. This dogma was all around during the 1990s of the last millennium. Some brave individuals nevertheless pursued the idea of identifying and developing kinase inhibitors for biologically highly interesting targets, such as p38 kinases [3] and protein kinase C (PKC) isoforms [4]. Although these were groundbreaking efforts in drug discovery in those early days, p38 and PKC inhibitors have never really made it beyond the status of tool compounds for biological research and chemical biology so far. At the end, a rather serendipitous finding started the race toward the competitive generation of kinase inhibitors in oncology. The introduction of a simple methyl group into a diaminopyrimidine scaffold of a known protein kinase C inhibitor led to the generation of a relatively specific Bcr-Abl inhibitor, called imatinib or Gleevec™. The fusion protein Bcr-Abl has been known as the driving oncogene in chronic myeloid leukemias (CML) with a mutation on the Philadelphia chromosome [5], which is mediated by the elevated Abl activity of the mutant. Subsequently, imatinib has shown convincing efficacy in treating CML patients [6]. A new era started when imatinib was launched in 2001 as the first specifically designed small-molecule kinase inhibitor. The second beneficial serendipity during the generation and development of imatinib was understood only slowly. Imatinib is not just a plain and simple ATP competitor as most kinase inhibitors were designed to be. It binds to the inactive form of Bcr-Abl and keeps the kinase in its inactive conformation [7]. Today, this phenomenon is not only much better understood but also considered to be an important design element when synthesizing novel kinase inhibitors. Both serendipitous features of imatinib, inhibition of Bcr-Abl and binding to the inactive kinase, paved the way for the establishment of its clinical efficacy. However, this success gave birth to another dogma that kinase inhibitors will be useful only for developing anticancer therapies. This second dogma was based on two assumptions: (1). since 2001, imatinib has been considered to be among the most selective kinase inhibitors although it potently inhibits at least a dozen other protein kinases [8]; (2) “ATP-competitive inhibitors are never going to be highly selective, because they bind to the highly conserved active domain of kinases”. Especially, the second point on the lack of selectivity was and still is highly speculative and led to the conclusion that nonselective kinase inhibitors cannot be used as treatment options in indication areas outside cancer because of their naturally invoked off-target mediated adverse effects. This assumption vice versa also led to the conclusion that nonselective but potent kinase inhibitors will be effective cancer killing agents. We would like to challenge these hypotheses for a number of reasons:

Kinase inhibitor technologies quickly advanced, especially compound design technologies, facilitated by the development of molecular modeling and X-ray resolutions of a large number of kinase inhibitor cocrystals (www.pdb.org/pdb/home/home.do).Exploitation of inhibitor binding to the inactive form of a kinase (type II inhibitors) has become an accepted design strategy and leads to a number of advantages in the pharmacological development of kinase inhibitors.Monoselective ATP competitors (type I inhibitors) have been generated, despite the fact that they bind only to the active site of a kinase [9].A fair number of scaffolds are known to compete with ATP for binding to the kinase active site, allowing a quick screening effort to identify potential starting points for a subsequent optimization program on practically any kinase.Allosteric kinase inhibitors have been reported to be an option for further development [10].The correlation between kinase homology and parallel structure–activity relationship tends to be understood much better [11].Nowadays, kinase inhibitor design can be envisioned as the molecular game with Lego bricks – and it really works.

Over these past years, we have been able to generate highly specific kinase inhibitors [12]. Since kinases play a role not only in carcinogenesis but also in all sorts of physiologically relevant signaling pathways [13], we are convinced that both oncology and any other medical indication might represent an important playground for the application of selective and safe kinase inhibitors. Future will demonstrate that kinase inhibitors are going to be applied to treat chronic conditions and not only in life-threatening settings. Therefore, we have chosen contributions to this book that describe the generation and application of kinase inhibitors also outside the important field of anticancer drug discovery. Broadly specific kinase inhibitors, such as sunitinib, will not have a chance for development for indications other than cancer. Instead, monoselective kinase inhibitors or multikinase inhibitors with a narrow profile will turn out to be efficacious if the chosen target is critical enough in a particular pathophysiological process. It is more about the validation of the target(s) and the underlying target(s) rationale. In that respect, it remains to be seen if p38α turns out to be a valid target for rheumatic arthritis or to be valid only for some distinct inflammatory diseases. The odds are that p38α inhibitors will not reach the status of a general anti-inflammatory agent due to target-mediated toxicities [14]. Although all p38α inhibitor research might then be considered a lost investment, it has nonetheless contributed enormously to the general strategies in developing kinase inhibitors, such as the directed design of type II inhibitors and the generation of highly selective kinase inhibitors, as well as their translation into pharmacologically active substances (e.g., [15]). These efforts significantly helped to pave the way for the development of highly selective future kinase inhibitors for different kinase targets without target-mediated toxicities. The world of protein kinases consists of more than, 500 individual members, the human kinome [16], therapeutically relevant parasitic kinase targets even not considered. Therefore, our prediction is that we will see many more novel drug candidates and pharmaceutical products arising from this large and important family of enzymes.

This gives hope to millions of patients suffering not only from various cancers but also from inflammatory, metabolic, and neurological disorders and infectious diseases, where a distinct kinase is out of control and must be tamed by a highly specific and potent kinase inhibitor. But what makes a good inhibitor? Which steps have to be taken for identifying a target and successfully making a drug with, if possible, no side effects? Which kinase inhibitors have been developed so far by using which design strategy? Can we already define lessons learned?

Small molecules and their apparently endless modularity and flexibility to produce all necessary structures are the perfect source for developing kinase inhibitors. Libraries of thousands to millions of compounds can be screened easily in high-throughput screens (HTS) or even in silico. Detected hits can be optimized step-by-step in iterative cycles toward highly potent and specific preclinical candidates and well-tolerated drugs on the market (or toward specific probes and tools in basic research). Thus, this book is dedicated to small-molecules kinase inhibitors and their various contributions to medical application.

Literature is exploding in the kinase inhibitor field, particularly when dealing with appropriate tools and design. In order to give a comprehensive overview about this special but diverse inhibitor species, this book covers the most important criteria from assay development to profiling and from medicinal chemistry-based optimization to a potential application. This book has been arranged in a logical order in various parts to highlight

hit finding and profiling for protein kinases, describing the Dos and Don'ts while identifying and (cellular) profiling of active small-molecule kinase inhibitors.chemical kinomics to detect phosphorylation networks.medicinal chemistry, offering a detailed summary of existing kinase inhibitors, available technologies, and design principles that might be considered.application to therapeutic indication areas, discussing in detail success stories and unmet needs in medical application including cancer, inflammatory diseases, and infections.

Thanks to the enthusiasm and the perseverance of the authors and the publisher of this book, we finally made it. Somehow, the genesis of this small compendium on kinase inhibitor research resembles the field of small-molecule-based kinase inhibitors itself. Some brave individuals quickly wrote and delivered their contributions within a short period of time, some others took more time to develop their chapters, and finally, some opted out of the project and were replaced by others who maybe considered newcomers to the field. This process seemed to reflect the development of the field of kinase inhibitor research over the past 15 years in nice analogy. On purpose, we have selected contributions on kinase inhibitor drug discovery from early-stage discoveries since there have been a lot of writing and comprehensive reviews on successfully launched kinase inhibitors, such as Gleevec, Iressa, Tarceva, Sorafenib, Sutent, Dasatinib, Lapatinib, and others ([1, 2] and references therein). There is also a good body of literature available on kinase inhibitors in cancer drug discovery. So, we rather focused both on the technologies for the discovery of kinase inhibitors and on the optimization of these inhibitors, and we included novel potential therapeutic applications of kinase inhibitors, especially fields outside the cancer research. Therefore, this collection of articles is quite unique, albeit highly representative when it comes to the identification and generation of novel kinase inhibitors with biological and pharmacological activity.

In the different chapters, experts in their field summarize the historical evolution, the trends, and a good part of their own experience gained while working in their respective fields. After reading the book, it will become clear how much promise small-molecule kinase inhibitors really hold, not only for the described therapeutic indications but also beyond, when obeying basic, intrinsic rules.

We are convinced that small-molecule kinase inhibitors will become ever more important in the years to come and are going to celebrate new success stories for research and patients – despite or even because of the current dramatic changes in pharmaceutical industry. Enjoy reading!

References

1. Pytel, D., Sliwinski, T., Poplawski, T., Ferriola, D., and Majsterek, I. (2009) Tyrosine kinase blockers: new hope for successful cancer therapy. Anti-Cancer Agents in Medicinal Chemistry, 9, 66–76.

2. Natoli, C., Perrucci, B., Perrotti, F., Falchi, L., Iacobelli, S., and Consorzio Interuniversitario Nazionale per Bio-Oncologia (CINBO) (2010) Tyrosine kinase inhibitors. Current Cancer Drug Targets, 10, 462–483.

3. Lee, J.C., Laydon, J.T., McDonnell, P.C., Gallagher, T.F., Kumar, S., Green, D., McNulty, D., Blumenthal, M.J., Heys, J.R., Landvatter, S.W., Strickler, J.E., McLaughlin, M.M., Siemens, I.R., Fisher, S.M., Livi, G.P., White, J.R., Adams, J.L., and Young, P.R. (1994) A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature, 372, 739–746.

4. Kawamoto, S. and Hidaka, H., (1984) 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine (H-7) is a selective inhibitor of protein kinase C in rabbit platelets. Biochemical and Biophysical Research Communications, 125, 258–264.

5. Heisterkamp, N., Stam, K., Groffen, J., de Klein, A., and Grosveld, G. (1985) Structural organization of the bcr gene and its role in the Ph' translocation. Nature, 315, 758–761.

6. Druker, B.J., Talpaz, M., Resta, D.J., Peng, B., Buchdunger, E., Ford, J.M., Lydon, N.B., Kantarjian, H., Capdeville, R., Ohno-Jones, S., and Sawyers, C.L. (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. The New England Journal of Medicine, 344, 1031–1037.

7. Dietrich, J., Hulme, C., and Hurley, L.H. (2010) The design, synthesis, and evaluation of 8 hybrid DFG-out allosteric kinase inhibitors: a structural analysis of the binding interactions of Gleevec, Nexavar, and BIRB-796. Bioorganic and Medicinal Chemistry, 18, 5738–5748.

8. Fabian, M.A., Biggs, W.H., 3rd, Treiber, D.K., Atteridge, C.E., Azimioara, M.D., Benedetti, M.G., Carter, T.A., Ciceri, P., Edeen, P.T., Floyd, M., Ford, J.M., Galvin, M., Gerlach, J.L., Grotzfeld, R.M., Herrgard, S., Insko, D.E., Insko, M.A., Lai, A.G., Lélias, J.M., Mehta, S.A., Milanov, Z.V., Velasco, A.M., Wodicka, L.M., Patel, H.K., Zarrinkar, P.P., and Lockhart, D.J. (2005) A small molecule-kinase interaction map for clinical kinase inhibitors. Nature Biotechnology, 23, 329–336.

9. Walburger, A., Koul, A., Ferrari, G., Nguyen, L., Prescianotto-Baschong, C., Huygen, K., Klebl, B., Thompson, C., Bacher, G., and Pieters, J. (2004) Protein kinase G from pathogenic mycobacteria promotes survival within macrophages. Science, 304, 1800–1804.

10. Lindsley, C.W., Zhao, Z., Leister, W.H., Robinson, R.G., Barnett, S.F., Defeo-Jones, D., Jones, R.E., Hartman, G.D., Huff, J.R., Huber, H.E., and Duggan, M.E. (2005) Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors. Bioorganic & Medicinal Chemistry Letters, 15, 761–764.

11. Vieth, M., Higgs, R.E., Robertson, D.H., Shapiro, M., Gragg, E.A., and Hemmerle, H. (2004) Kinomics: structural biology and chemogenomics of kinase inhibitors and targets. Biochimica et Biophysica Acta, 1697, 243–257.

12. Wabnitz, P. et al. (2008) 4,6-Disubstituted aminopyrimidine derivatives as inhibitors of protein kinases. WO/2008/129080.

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October 2010

Bert Klebl, (Dortmund)Gerhard Müller, (Planegg)Michael Hamacher, (Dortmund)

Part One

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