Contents
PREFACE
ACKNOWLEDGMENTS
CHAPTER 1 KINASES AND CANCER
1.1 A BRIEF HISTORY OF PROTEIN PHOSPHORYLATION
1.2 KINASES AND CANCER
1.3 A TOUR OF THE HUMAN PROTEIN KINASE SUPERFAMILY
1.4 STRATEGIC CONSIDERATIONS FOR SELECTING KINASES AS DRUG TARGETS
1.5 COMPARISON OF KINASE INHIBITOR THERAPEUTIC STRATEGIES
REFERENCES
CHAPTER 2 PROTEIN KINASE STRUCTURE, FUNCTION, AND REGULATION
2.1 LIGAND BINDING TO RECEPTOR TYROSINE KINASES
2.2 PROTEIN KINASE DOMAIN STRUCTURE AND FUNCTION
2.3 CATALYTIC ACTIVITY OF PROTEIN KINASES
2.4 PROTEIN KINASE REGULATION
REFERENCES
CHAPTER 3 RECEPTOR TYROSINE KINASES
3.1 EGF/ERBB RECEPTORS
3.2 INSULIN/IGF RECEPTORS
3.3 ANAPLASTICLYMPHOMAKINASE
3.4 VEGF RECEPTORS (VEGFR1, VEGFR2, VEGFR3)
3.5 PDGF RECEPTORS
3.6 FGF RECEPTORS
3.7 KIT
3.8 FLT3
3.9 RET
3.10 METAND RON
REFERENCES
CHAPTER 4 NONRECEPTOR TYROSINE KINASES
4.1 ABL
4.2 ARG
4.3 SRC AND SRC FAMILY KINASES
4.4 FAK
4.5 JAK
REFERENCES
CHAPTER 5 INTRACELLULAR SIGNAL TRANSDUCTION CASCADES
5.1 THE PI3K/PTEN PATHWAY
5.2 mTOR SIGNALING
5.3 MAPK SIGNALING PATHWAYS
5.4 PIM KINASES
5.5 PROTEIN KINASEC
REFERENCES
CHAPTER 6 CELL CYCLE CONTROL
6.1 CYCLIN-DEPENDENT KINASES (CDKS) AND CELL CYCLE PROGRESSION
6.2 CDKS AND mRNA PRODUCTION
6.3 OTHER CDK-RELATED KINASES
6.4 MITOTIC KINASES
6.5 CELL CYCLE CHECKPOINT KINASES
REFERENCES
CHAPTER 7 STRUCTURAL BIOCHEMISTRY OF KINASE INHIBITORS
7.1 STRATEGIES FOR INHIBITOR DESIGN
7.2 ARCHITECTURE OF THE ATP BINDING SITE: DFG-in
7.3 CASE STUDY: INHIBITORS OF CHK1
7.4 CASE STUDY: INHIBITORS OF CDK2
7.5 CASE STUDY: INHIBITORS OF SRC FAMILY KINASES
7.6 CASE STUDY: EGF RECEPTOR INHIBITORS
7.7 TARGETING THE INACTIVE CONFORMATION
7.8 NONCOMPETITIVE INHIBITION
7.9 KINASE INHIBITOR SPECIFICITY
REFERENCES
CHAPTER 8 TYROSINE KINASE INHIBITORS
8.1 BCR-ABL INHIBITORS
8.2 SRC INHIBITORS
8.3 JAK2 INHIBITORS
8.4 EGFR/ERBB INHIBITORS
8.5 IGF1R INHIBITORS
8.6 FLT3 INHIBITORS
8.7 KIT INHIBITORS
8.8 MET/RON INHIBITORS
8.9 RET INHIBITORS
8.10 OTHER INHIBITORS
REFERENCES
CHAPTER 9 ANGIOKINASE INHIBITORS
9.1 INTRODUCTION
9.2 ANGIOKINASE INHIBITORS
REFERENCES
CHAPTER 10 INTRACELLULAR SIGNALING KINASE INHIBITORS
10.1 mTOR INGIBITORS
10.2 PI3K INHIBITORS
10.3 RAF KINASE INHIBITORS
10.4 MEK INHIBITORS
10.5 CDK INHIBITORS
10.6 CELL CYCLE CHECKPOINT KINASE INHIBITORS
10.7 MITOTIC KINASE INHIBITORS
10.8 PROTEIN KINASE C INHIBITORS
REFERENCES
CHAPTER 11 CURRENT CHALLENGES AND FUTURE DIRECTIONS
11.1 KINASE INHIBITOR DRUG RESISTANCE
11.2 COMBINATION THERAPY WITH KINASE
11.3 SYSTEMS BIOLOGY AND TRANSLATIONAL
11.4 CONCLUSIONS
REFERENCES
LIST OF ABBREVIATIONS
APPENDIX I: TUMOR ASSOCIATED MUTATIONS IN EGFR
APPENDIX II: TUMOR ASSOCIATED MUTATIONS IN ERBB2
APPENDIX III: TUMOR ASSOCIATED MUTATIONS IN ALK
APPENDIX IV: TUMOR ASSOCIATED MUTATIONS IN PDGFRα
APPENDIX V: TUMOR ASSOCIATED MUTATIONS IN FGFR1
APPENDIX VI: TUMOR ASSOCIATED MUTATIONS IN FGFR2
APPENDIX VII: TUMOR ASSOCIATED MUTATIONS IN FGFR3
APPENDIX VIII: TUMOR ASSOCIATED MUTATIONS IN FGFR4
APPENDIX IX: TUMOR ASSOCIATED MUTATIONS IN KIT
APPENDIX X: TUMOR ASSOCIATED MUTATIONS IN FLT3
APPENDIX XI: TUMOR ASSOCIATED MUTATIONS IN RET
APPENDIX XII: TUMOR ASSOCIATED MUTATIONS IN MET
APPENDIX XIII: TUMOR ASSOCIATED MUTATIONS IN JAK2
APPENDIX XIV: TUMOR ASSOCIATED MUTATIONS IN PIK3CA
APPENDIX XV: TUMOR ASSOCIATED MUTATIONS IN BRAF
APPENDIX XVI: TUMOR ASSOCIATED KINASE DOMAIN MUTATIONS IN ABL
INDEX
Copyright © 2010 by John Wiley & Sons, Inc. All rights reserved
Published by John Wiley & Sons, Inc., Hoboken, New Jersey
Published simultaneously in Canada.
No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permission Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission.
Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein man not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.
For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002.
Wiley also publishes its books in a variety of electronic formats. Some Content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com.
Library of Congress Cataloging-in-Publication Data:
Matthews, David J. (David John), 1965-
Targeting protein kinases for cancer therapy / David J. Matthews, Mary E. Gerritsen.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-0-470-22965-1 (cloth)
1. Protein kinases–Inhibitors–Therapeutic use. 2. Antineoplastic agents. 3. Protein kinases. I. Gerritsen, Mary E. II. Title.
[DNLM: 1. Neoplasms–drug therapy. 2. Protein Kinase Inhibitors–therapeutic use. 3. Drug Discovery. 4. Drug Resistance, Neoplasm. 5. Protein Kinases–physiology. 6. Protein-Tyrosine Kinases–antagonists & inhibitors. QZ 267M438t 2009]
RC271.P76M38 2009
615′.798–dc22
2009020804
PREFACE
Protein kinases are among the most critical and widely studied cellular signaling molecules and regulate essentially all processes central to the growth, development, and homeostasis of eukaryotic cells. In the 1980s, protein kinases were first shown to have an important role in oncogenesis and tumor progression, and since then they have received increasing attention as targets for anticancer drugs. Several kinase inhibitors are now approved for the treatment of cancer, and many more are advancing through clinical trials. In Targeting Protein Kinases for Cancer Therapy, we provide an integrated view of kinase cancer targets and the drugs that inhibit them, with a focus on small molecule inhibitors. We have sought to cover the field broadly, and although some targets, pathways, and drugs are covered in depth, some have of necessity only been covered briefly. We have included many references to both review articles and primary literature, but apologize to colleagues whose work could not be cited due to limitations of space.
Throughout this book, proteins are denoted by their most widely accepted abbreviation in capital letters (see List of Abbreviations) and often additional names by which the protein is known are also provided. The human genes (using the abbreviations of the Human Genome Nomenclature Committee (www.genenames.org)) are denoted by italic capital letters. Genes from lower organisms are denoted by italic lowercase letters. Viral proteins or genes are denoted by the prefix v-. Protein kinase structures (discussed mainly in Chapters 2 and 7) are referenced by their protein data bank (PDB) accession code and can be accessed at www.rcsb.org.
In Chapter 1, we review the human kinome—the superfamily of over 500 protein kinases, many of which have been implicated in tumorigenesis and the proliferation and survival of cancer cells. We also consider various approaches for the discovery and validation of kinase cancer targets, and some of the therapeutic modalities that have been employed apart from small molecule inhibitors of kinase domains. Here we meet a recurring theme: many kinases appear to be dual agents with regard to cancer, in that depending on the cellular context in which they operate, they can either promote or inhibit tumor formation and progression. Chapter 2 introduces the structural features of protein kinases. We discuss various modes of receptor:ligand interaction used by receptor tyrosine kinases, then turn our attention to the catalytic properties and various regulatory mechanisms of the kinase catalytic domain itself. Chapter 3 presents a review of some prominent receptor tyrosine kinases, which to date have received the most attention as cancer targets. In Chapter 4, we move inside the cell membrane and focus on the non-receptor tyrosine kinases. Chapters 5 and 6 introduce various intracellular kinase signaling pathways that are dysregulated in tumor cells and that have received significant attention for the development of anticancer drugs. These include a complex, interconnected signaling network downstream of cell surface receptors, as well as circuits that control transit through the cell cycle, cell division, and DNA repair. In Chapter 7, we revisit kinase structure but with a focus on the design of small molecule inhibitors. Various binding modes have been discovered and are discussed along with their implications for achieving potency and selectivity. Chapters 8-10 discuss many of the kinase inhibitors that have entered clinical trials for treatment of cancer, with an emphasis on those molecules that have progressed to late stage clinical trials and, in a few cases, to market. We have categorized these drugs by their primary cognate targets: tumor cell tyrosine kinase inhibitors in Chapter 8, angiogenesis (“angiokinase”) inhibitors in Chapter 9, and intracellular pathway inhibitors in Chapter 10. However, since many of the inhibitors discussed have multiple targets, there are many overlaps between these categories, as indicated by the extensive cross-referencing between these chapters. In Chapter 11, we conclude by considering some of the challenges facing the field of oncology kinase inhibitor discovery. Although there have been some notable successes, drug resistance has emerged as a substantial impediment to achieving profound and durable responses in patients. We consider some of the strategies to address this, in particular, the use of combination therapy regimens that may simultaneously target multiple pathways and mechanisms. Such approaches rely on a thorough understanding of the underlying biology, and we focus on two prominent areas that are driving this knowledge forward: systems biology and translational medicine.
DAVID J. MATTHEWS
MARY E. GERRITSEN
So. San Francisco, California November 2009
ACKNOWLEDGMENTS
Many of our colleagues have provided indispensable assistance in the preparation of this work. We thank Glenn Hammonds and Joanne Adamkewicz for help with bioin-formatics and preparation of figures (in particular, the dendrograms in Chapter 1, the kinase domain diagrams throughout the book, and the appendices), and Thomas Stout for the molecular graphics figures on the front cover and in Chapters 2, 5 and 7; thanks also to Dr. Marat Valiev for supplying Figure 2.5B. Michael Ollmann wrote much of the target validation discussion (Chapter 1); Robert Blake provided helpful suggestions regarding target validation and also contributed to the section on SRC kinase (Chapter 4). Kwang-Ai Won and Timothy Heuer provided much of the cyclin-dependent kinase review (Chapter 6); Ross Francis, Peiwen Yu, Vanessa Lemahieu, Sophia Kuo, Michael Ollmann, Scott Detmer, Timothy Heuer, and Garth McGrath assisted in preparation of the appendices. We thank Paul Foster, Stuart Johnston, and Scott Robertson, whose work formed the basis for the discussions of PI-3 kinase, RAF/MEK kinases, and CDC7, respectively. We also thank Dana Aftab for helpful discussions regarding translational medicine, and Peter Lamb and Michael Morrissey for their encouragement and support. Many others have provided expert review of various chapters (although we take sole responsibility for any errors herein), including Robert Blake, Richard Cutler, Scott Detmer, Art Hanel, Timothy Heuer, Douglas Laird, Sophia Kuo, Vanessa Lemahieu, Nicole Miller, John Nuss, Michael Ollmann, Obdulio Piloto, Thomas Stout, Valentina Vysotskaia, Ron Weitzman, Kwang-Ai Won, and Peiwen Yu.
The views expressed in this book are those of the authors and do not represent the views of Exelixis, Inc.
D. J. M.
M. E. G.