Targeting Protein Kinases for Cancer Therapy ebook

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

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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.

CHAPTER 1

KINASES AND CANCER

1.1 A BRIEF HISTORY OF PROTEIN PHOSPHORYLATION

The importance of phosphorus in cellular metabolism has been appreciated for over 100 years, since inorganic phosphate was shown to be a prerequisite for fermentation by yeast (1). Over the ensuing decades high energy phosphate esters, in particular, adenosine triphosphate (ATP), were recognized as central sources of cellular free energy. ATP is present in cells at a concentration of 1 to 5 mM (2, 3), and its hydrolysis to adenosine diphosphate (ADP) and inorganic phosphate is central to almost all cellular processes and pathways.

By the early 1950s, it was clear that proteins could incorporate phosphorus into their structures. Moreover, it appeared that the phosphorus in the “phospho-protein fraction” was labile and was rapidly turned over in living cells (4, 5). The site of protein phosphorylation was initially shown to be serine residues (6), and in 1954 George Burnett and Eugene Kennedy described an enzyme extract from rat liver mitochondria that catalyzed the phosphorylation of a protein substrate (casein) by ATP (7). Around this time, Edmond Fischer and Edwin Krebs were studying the biochemistry of glycogen phosphorylase from skeletal muscle, an enzyme that releases glucose from intracellular glycogen stores and plays a critical role in the cellular energy supply. Glycogen phosphorylase was known to exist in two forms: the inactive glycogen phosphorylase b and the active glycogen phosphorylase a. Fischer and Krebs showed that the conversion of glycogen phosphorylase b to a was catalyzed by an enzyme that they called phosphorylase kinase, which transferred the γ-phosphate of ATP to the protein (8, 9) (Figure 1.1). This was the first demonstration that protein kinases play a key role in regulating biochemical signaling pathways, and in 1992 Krebs and Fischer were awarded the Nobel Prize in physiology/medicine “for their discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism” (10, 11).

Phosphorylase kinase was subsequently found to be phosphorylated and activated by another kinase, cAMP-dependent protein kinase (PKA) (12). This was the first demonstration of a protein kinase cascade, which has since been found to be a widespread mechanism for controlling the diversity and specificity of intracellular kinase signaling pathways. PKA represents a landmark in kinase research in several other ways. It was the first kinase for which a consensus substrate sequence was identified (R-R-X-S-X, where X represents any amino acid (13–16)), and the first kinase for which the complete amino acid sequence was determined (17). Furthermore, in 1991 Susan Taylor and colleagues determined the structure of PKA using X-ray crystallography, providing the first insight into the molecular architecture of protein kinases and the structural basis for their activity (18).

In the early 1980s, the repertoire of protein kinase functions was expanded with the discovery that some kinases phosphorylate tyrosine residues instead of ser-ines. It had previously been shown that the oncogenic Rous sarcoma virus encoded a gene with homology to protein kinases, and that the product of this gene, designated pp60SRC, was responsible for the oncogenicity of the virus (19–21). Tony Hunter and colleagues showed that pp60SRC is a tyrosine kinase, and that its kinase activity is critical for cellular transformation by the virus (22, 23). In the same year, Stanley Cohen and colleagues showed that epidermal growth factor receptor (EGFR) is also a tyrosine kinase (24). Many tyrosine kinases of both the receptor and non receptor variety have subsequently been identified, and in addition to performing critical cellular signaling functions in normal cells they have emerged as a particularly important group of kinases in multiple aspects of tumor biology. Although most kinases can broadly be classified as either serine/threonine or tyrosine kinases, there are several instances of kinases that can accept either serine/threonine or tyrosine as a substrate. Notable examples include the mitogen activated protein kinase kinases (MAPKKs, or MAP2Ks), which phosphorylate their substrates on both threonine and tyrosine residues of a T-X-Y motif. Protein kinases are highly conserved among mammalian species and have significant homology with related proteins from other metazoans, yeast, plants, and all of the major eukaryotic kingdoms. (Lower eukaryotes also express protein histidine kinases, which autophosphorylate on histidine residues and transfer the phosphate group to an aspartate residue in a receiver protein (25). These are related to prokaryotic proteins with similar function but are not part of the protein kinase superfamily, and we will not consider them further.)

Eukaryotic protein kinase domains are comprised of 250–300 amino acids residues and have characteristic regions of conserved sequence that have been used to both characterize functionally important regions and to determine phylogenetic relationships between the various kinases (26, 27). Initial sequence analysis of kinases from various eukaryotes revealed the presence of 12 conserved subdomains (typically referred to by roman numerals I–XI; subdomain VI is further divided into VIA and VIB). X-ray crystal structures subsequently revealed that kinase domains are comprised of two major lobes, with the ATP binding site and catalytic machinery lying at the interface of the two lobes (Figure 2.3). Subdomains I–V constitute the N-terminal lobe of the kinase and subdomains V-XI the C-terminal lobe. Of particular note, subdomain I contains a conserved glycine-rich region that forms part of the nucleotide binding site. Subdomains II and III contain a highly conserved lysine and glutamate residue, respectively, which together form a salt bridge that interacts with ATP. The formation and disruption of this salt bridge forms an important part of the regulatory mechanism for many kinases. Subdomain VIB contains an invariant aspartate residue that acts as the catalytic base and a conserved asparagine that helps to orient the catalytic aspartate. Subdomain VII contains a characteristic “DFG” sequence, which marks the start of the so-called activation segment, another important feature in regulation of kinase activity. The aspartate of the DFG motif is another important catalytic residue that coordinates a divalent cation in the active site. Further details of protein kinase structure and catalytic mechanism are presented in Chapter 2.