Protein Kinases: Technologies and Opportunities for Drug Discovery.

Protein Kinases: Technologies and Opportunities for Drug Discovery.

Publisher:	D&MD Publications Inc
Year of publication:	2003
Type of publication:	Management report
Publisher's reference (if any):	D&MD9119
Author(s):	Sreten Bogdanovic and Beata Langlands
Approximate page count:	300
Price when published:	$4,950
Remarks: Page numbers, where given, refer to the draft manuscript (which may differ from the published version). The copyright in this report is owned by the publisher, to whom any requests for copies should be addressed. The price shown is for a single copy of the print version. Multiple copies and electronic copies usually have different prices.
PROTEIN KINASES Technologies and Opportunities for Drug Discovery TABLE OF CONTENTS CHAPTER 1 PROTEIN KINASES AND CELL SIGNALING 1.1 Introduction 1.2 Human protein kinases 1.2.1 Classification 1.2.2 Catalytic and interaction domains 1.2.3 Cystolic and receptor kinases 1.3 Human protein phosphatases 1.4 Signal transduction pathways 1.4.1 MAP kinase pathways 1.4.1.1 MAPK(ERK) pathway 1.4.1.2 JNK/SAPK pathway 1.4.1.3 p38 MAPK pathway 1.4.2 PI3K/Akt signaling 1.4.3 Jak/STAT signaling 1.4.3.1 Jak/STAT3 signaling in cancer 1.4.4 Insulin Receptor Signaling 1.4.5 NF-B pathway 1.4.5.1 TNF signaling in cancer 1.4.6 Immune cell signaling 1.4.6.1 T Cell Receptor signaling 1.4.6.2 B-Cell Receptor Complexes 1.4.7 Signaling in vascular morphogenesis 1.4.7.1 VEGF receptor signaling 1.4.8 EGF receptor signaling 1.4.9 Cyclic nucleotide metabolism 1.4.10 Cell cycle checkpoint controls 1.5 Development of protein kinase inhibitors 1.6 Diseases associated with dysfunctional kinases 1.7 Scope of this report CHAPTER 2 TECHNOLOGIES FOR STUDYING PROTEIN KINASES 2.1 Proteomics 2.1.1 Objectives 2.1.2 Relationship to genomics 2.1.3 Uses of proteomics 2.1.4 Proteomic technologies 2.1.5 Separation technologies - 2DE, HPLC, CE, and arrays 2.1.6 Sample variability 2.1.7 Protein identification by mass spectrometry 2.1.8 Determination of 3D protein kinase structures 2.1.8.1 Introduction to protein structure determination 2.1.8.2 X-Ray Crystal Diffraction 2.1.8.2 Solution NMR 2.1.8.3 Theoretical modelling 2.1.8.4 Commercial uses of structure data 2.1.9 Peptide chips for monitoring kinase activity 2.2 Cellomics 2.2.1 Introduction 2.2.2 Uses of cellomics 2.2.3 Cellomics technolgies CHAPTER 3 STRATEGIES FOR KINASE DRUG DISCOVERY 3.1 General introduction 3.1.1 Small molecule drugs 3.1.2 Biopharmaceuticals 3.1.2.1 Antisense therapy 3.1.2.2 RNA interference 3.1.2.2 Monoclonal antibodies 3.1.3 Genomics-based approaches 3.1.4 Proteomics-based approaches 3.1.5 The role of SNP scoring 3.2 Discovery of small molecule kinase inhibitors 3.2.1 Trends in target identification 3.2.2 Trends in target validation 3.2.3 Trends in lead generation 3.2.4 Trends in lead optimization 3.2.5 Integrated use of technologies 3.2.5.1 Chemical genomics 3.2.6 Establishing inhibitor specificity 3.2.7 Identifying substrates of kinases 3.2.8 Preclinical and clinical development 3.2.8.1 The use of surrogate biomarkers 3.3 Companion drug/theranostic approach CHAPTER 4 PROTEIN KINASE TARGETS IN CANCER 4.1 Overview of cancer 4.1.1 Oncogenes and tumor suppressor genes 4.1.2 Established therapies 4.2 Molecular targeted therapies 4.2.1 Dysfunctional kinases and cancer 4.3 Current kinase drug targets 4.3.1 EGFR family 4.3.1.1 Antibody drugs 4.3.1.2 Small molecule drugs 4.3.2 Kinases in hematologic malignancies 4.3.2.1 Abl 4.3.2.2 Flt-3 4.3.2.3 c-kit 4.3.3 Angiogenic tyrosine kinases 4.3.3.1 VEGFR 4.3.3.2 Other kinases 4.3.4 PKC family 4.3.5 CDK family 4.3.6 PIK-related family 4.3.7 PKA family 4.3.8 Kinases in Raf/MAPK pathway 4.3.9 Kinases in PI3K/Akt pathway 4.3.10 Kinases in NF-B pathway 4.3.11 Kinases in JNK/SAPK pathway 4.3.12 Src family 4.3.13 Aurora family 4.3.14 Other kinase targets 4.4 Tyrosine phosphatases 4.5 Kinase profiling of cancers CHAPTER 5 PROTEIN KINASE TARGETS IN OTHER DISEASES 5.1 Inflammation and tissue injury 5.1.1 Introduction 5.1.1.1 Current treatments 5.1.2 Kinase targets 5.1.2.1 p38 MAPK 5.1.2.2 JNKs 5.1.2.3 IKK 5.1.2.4 Other kinase targets 5.1.3 Phosphatase targets 5.2 Diabetes and insulin resistance 5.2.1 Introduction 5.2.2 Current treatments 5.2.3 Involvement of stress pathways 5.2.4 Kinase targets 5.2.4.1 PKC-beta and VEGFR 5.2.4.2 c-raf 5.2.4.3 Insulin receptor 5.2.4.4 GSK-3 5.2.4.5 GRK 5.2.5 Phosphatase targets 5.3 Neurological diseases and stroke 5.3.1 Introduction 5.3.2 Kinase targets 5.3.2.1 Kinases in JNK/SAPK pathway 5.3.2.2 CK-1 5.3.2.3 GSK-3beta 5.3.2.4 p38 MAPK 5.4 Osteoporosis and related bone diseases 5.4.1 Introduction 5.4.2 Src kinase 5.5 Other diseases 5.5.1 Septic shock 5.5.2 Bacterial infections 5.5.3 Viral infections 5.5.4 Macular degeneration 5.5.5 Cardiac hypertrophy 5.6 New directions CHAPTER 6 MARKET CONSIDERATIONS AND FORECASTS 6.1 Overview of the major markets 6.1.1 Global population growth 6.1.2 The US healthcare market 6.1.3 The Japanese healthcare market 6.1.4 The European healthcare markets 6.1.4.1 Germany 6.1.4.2 France 6.1.4.3 Italy 6.1.4.4 United Kingdom 6.1.4.5 Spain 6.1.5 Emerging markets 6.1.6 Growth of pharma markets in 2002 6.2 Market forecasts by disease 6.2.1 Prevalence of targeted diseases 6.2.2 Cancer 6.2.2.1 The existing drug market 6.2.2.2 Market forecasts for kinase inhibitors 6.2.2.2.1 EGFR inhibitors 6.2.2.2.2 Protein kinases in hematologic malignancies 6.2.2.2.3 Angiogenic kinase receptors 6.2.2.2.4 PKC family 6.2.2.2.5 Other kinase targets 6.2.3 Inflammatory disorders 6.2.3.1 The existing market 6.2.3.2 Market forecasts for kinase inhibitors 6.2.4 Diabetic microvascular complications 6.3 Market forecasts by geographical region 6.4 Leading players CHAPTER 7 COMPANY PROFILES 7.1 Amgen Inc 7.2 ARIAD Pharmaceuticals Inc 7.3 ArQule Inc 7.4 AstraZeneca Plc 7.5 Axxima Pharmaceuticals AG 7.6 Biofocus plc 7.7 Celgene Corporation 7.8 Cellular Genomics Inc 7.9 Cephalon Inc 7.10 Eli Lilly and Co 7.11 eXegenics Inc 7.12 Genentech Inc 7.13 GlaxoSmithKline plc 7.14 Hybridon Inc 7.15 ICOS Corporation 7.16 ImClone Systems Inc 7.17 Incyte Corporation 7.18 Isis Pharmaceuticals Inc 7.19 Keryx Biopharmaceuticals Inc 7.20 Nanogen Inc 7.21 Novartis Pharma AG 7.22 Onyx Pharmaceuticals Inc 7.23 OSI Pharmaceuticals 7.24 Pfizer Inc 7.25 Scios Inc 7.26 Sirna Therapeutics Inc 7.27 Structural GenomiX 7.28 Syrrx Inc 7.29 Telik Inc 7.30 Vertex Pharmaceuticals Inc CHAPTER 8 TRENDS AND OPPORTUNITIES 8.1 The druggable kinase superfamily 8.2 Low toxicity agents 8.3 Young biotech companies driving innovation 8.4 Improving ATP-competitive inhibitors 8.5 Beyond ATP-competitive inhibition 8.6 Targeting the kinase activation site 8.7 Targeting kinase-substrate interactions 8.8 Future alternatives to small molecule drugs 8.9 Leukemias: market uptake regardless of price 8.10 Solid tumors: lessons learnt 8.11 Surrogate biomarkers: role in trials 8.12 Resistance creates commercial opportunities 8.13 Theranostic tests: key to therapy success 8.14 Towards kinase-based tumor profiling 8.15 Targeting activation profiles 8.16 Targeting splice variants 8.17 First kinase activators 8.18 Inflammation: challenge to biologics 8.19 Diabetes: many promising approaches 8.20 Extending the range of clinical indications 8.21 Unexplored kinase targets in cancer 8.22 Unexplored kinase targets in other diseases EXECUTIVE SUMMARY Protein kinases play a central role in diverse signal transduction pathways involved in the control of cell growth, metabolism, differentiation, and apoptosis. The 518 human protein kinase genes which were identified in 2002 offer a bewildering choice of potential kinase targets. Although this is nascent market, the first two widely launched agents, Genentech's Herceptin and Novartis' Gleevec, have already achieved combined sales of $1 billion in 2002. We are forecasting sales of $4.6 billion for 2007, mainly in the therapeutic area of cancer. Beginning with an overview of the kinase family and the signaling pathways in which kinases play a key role, this report comprehensively reviews and assesses kinase targets currently under commercial investigation, and highlights unexplored areas of opportunity. The scope is wide, covering small molecule, monoclonal antibody, antisense and RNA-based kinase inhibitors under commercial development for a broad range of clinical indications. Although most endeavour is currently directed at the development of kinase inhibitors, kinase activation is also of potential importance, and developments in this area are included. Kinase inhibitors under commercial development are directed at extracellular as well as intracellular kinase targets. Most agents target the kinase catalytic domain. We report on ongoing efforts to improve traditional ATP competitive inhibitors and develop alternative approaches to inhibition of kinase catalytic function. We also review traditional agents targeting extracellular ligand- binding kinase domains, as well as newer agents targeting kinase activation domains and substrate binding domains. Proteomic technologies are enabling rational drug design, providing new insights into conformational variability between kinases, and expanding our understanding of the role of kinases in health and disease. The rate of drug discovery in this area is set to accelerate. This is likely to be enabled by the growing trend to direct the early portion of the drug discovery process toward target gene families, rather than therapeutic areas. We review curent trends in kinase drug discovery, highlight promising proprietary approaches to target identification, target validation, lead generation, and lead optimization, and identify issues of special relevance to kinase drug discovery, such as inhibitor specificity, surrogate biomarkers, and substrate identification. Protein kinase genes are commonly mutated or dysregulated in cancer, and as a result rationally designed kinase inhibitors are set to be major players in the next generation of targeted cancer therapies. The trailblazing targeted anti-cancer kinase inhibitors Herceptin and Gleevec have given the world a foretaste of personalized medicine of the future. We review kinases which have been considered prime targets for the development of selective inhibitors - the epidermal growthfactor receptor kinase family, kinases involved in hematologic malignancies, kinases involved in the neo- vascularization of tumors, the protein kinase C family, and the cell cycle regulating kinases. The range of kinase targets has been steadily expanded to include other kinase families believed to play an important part in the etiology of cancer. We comment on positive findings as well as setbacks encountered and highlight areas of opportunity. Outside the cancer field, blockbuster potential resides in kinase- targeting drugs in late stages of clinical development for the treatment of inflammatory diseases and for the treatment of diabetic microvascular complications. In rheumatoidarthritis, potential challenge to injectable biologics comes in the form of orally active small molecule inhibitors of p38 kinase. Protein kinase C-targeting inhibitors in clinical trials address the causes of diabetic retinopathy, for which no treatments currently exist. Promising agents for treating insulin resistance associated with type 2 diabetes are also under investigation. The range of clinical indications for kinase inhibitors is being extended with preclinical studies and early stage clinical trials addressing diseases as diverse as neurodegenerative diseases, osteoporosis, macular degeneration, septic shock, bacterial infections, and viral infections. Despite the progress so far, many promising targets in cancer and other diseases remain unexplored. In 2002, the Human Kinome Project (HKP) published findings which revealed that 164 kinases map to cancer loci and a further 80 kinases map to loci implicated in other diseases. Many of those potential kinase targets in cancer have yet to be explored. Likewise, important non-malignant conditions associated with specific kinases identified by the HKP are not currently a major focus of investigation. The report profiles 30 key companies active in the kinase drug discovery, which includes small specialist companies, commercial- stage biotech companies, and large pharmaceutical companies. Information is provided on recent acquisitions and collaborations in this area. Although the report is focused on protein kinases, company profiles also contain information on drugs targeting protein phosphatases, which despite their potential importance, are currently few in number.

Publisher:

D&MD Publications Inc

Year of publication:

2003

Type of publication:

Management report

Publisher's reference (if any):

D&MD9119

Author(s):

Sreten Bogdanovic and Beata Langlands

Approximate page count:

300

Price when published:

$4,950

Remarks:

Page numbers, where given, refer to the draft manuscript (which may differ from the published version).
The copyright in this report is owned by the publisher, to whom any requests for copies should be addressed.
The price shown is for a single copy of the print version. Multiple copies and electronic copies usually have different prices.

                                PROTEIN KINASES
                Technologies and Opportunities for Drug Discovery

                               TABLE OF CONTENTS

         CHAPTER 1 PROTEIN KINASES AND CELL SIGNALING

           1.1 Introduction

           1.2 Human protein kinases
              1.2.1 Classification
              1.2.2 Catalytic and interaction domains
              1.2.3 Cystolic and receptor kinases

           1.3 Human protein phosphatases

           1.4 Signal transduction pathways
              1.4.1 MAP kinase pathways
                1.4.1.1 MAPK(ERK) pathway
                1.4.1.2 JNK/SAPK pathway
                1.4.1.3 p38 MAPK pathway
              1.4.2 PI3K/Akt signaling
              1.4.3 Jak/STAT signaling
                1.4.3.1 Jak/STAT3 signaling in cancer
              1.4.4 Insulin Receptor Signaling
              1.4.5 NF-B pathway
                1.4.5.1 TNF signaling in cancer
              1.4.6 Immune cell signaling
                1.4.6.1 T Cell Receptor signaling
                1.4.6.2 B-Cell Receptor Complexes
              1.4.7 Signaling in vascular morphogenesis
                1.4.7.1 VEGF receptor signaling
              1.4.8 EGF receptor signaling
              1.4.9 Cyclic nucleotide metabolism
              1.4.10 Cell cycle checkpoint controls

           1.5 Development of protein kinase inhibitors

           1.6 Diseases associated with dysfunctional kinases

           1.7 Scope of this report

         CHAPTER 2 TECHNOLOGIES FOR STUDYING PROTEIN KINASES

           2.1  Proteomics
              2.1.1  Objectives
              2.1.2  Relationship to genomics
              2.1.3  Uses of proteomics
              2.1.4  Proteomic technologies
              2.1.5  Separation technologies -
                     2DE, HPLC, CE, and arrays
              2.1.6  Sample variability
              2.1.7  Protein identification by mass spectrometry
              2.1.8 Determination of 3D protein kinase structures
                2.1.8.1 Introduction to protein structure
                        determination
                2.1.8.2 X-Ray Crystal Diffraction
                2.1.8.2 Solution NMR
                2.1.8.3 Theoretical modelling
                2.1.8.4 Commercial uses of structure data
              2.1.9 Peptide chips for monitoring kinase activity

           2.2  Cellomics
              2.2.1  Introduction
              2.2.2  Uses of cellomics
              2.2.3  Cellomics technolgies

         CHAPTER 3 STRATEGIES FOR KINASE DRUG DISCOVERY

           3.1 General introduction
              3.1.1 Small molecule drugs
              3.1.2 Biopharmaceuticals
                3.1.2.1 Antisense therapy
                3.1.2.2 RNA interference
                3.1.2.2 Monoclonal antibodies
              3.1.3 Genomics-based approaches
              3.1.4 Proteomics-based approaches
              3.1.5 The role of SNP scoring

           3.2 Discovery of small molecule kinase inhibitors
              3.2.1 Trends in target identification
              3.2.2 Trends in target validation
              3.2.3 Trends in lead generation
              3.2.4 Trends in lead optimization
              3.2.5 Integrated use of technologies
                3.2.5.1 Chemical genomics
              3.2.6 Establishing inhibitor specificity
              3.2.7 Identifying substrates of kinases
              3.2.8 Preclinical and clinical development
                3.2.8.1 The use of surrogate biomarkers

           3.3 Companion drug/theranostic approach

         CHAPTER 4 PROTEIN KINASE TARGETS IN CANCER

           4.1 Overview of cancer
              4.1.1 Oncogenes and tumor suppressor genes
              4.1.2 Established therapies

           4.2 Molecular targeted therapies
              4.2.1 Dysfunctional kinases and cancer

           4.3 Current kinase drug targets
              4.3.1 EGFR family
                4.3.1.1 Antibody drugs
                4.3.1.2 Small molecule drugs
              4.3.2 Kinases in hematologic malignancies
                4.3.2.1 Abl
                4.3.2.2 Flt-3
                4.3.2.3 c-kit
              4.3.3 Angiogenic tyrosine kinases
                4.3.3.1 VEGFR
                4.3.3.2 Other kinases
              4.3.4 PKC family
              4.3.5 CDK family
              4.3.6 PIK-related family
              4.3.7 PKA family
              4.3.8 Kinases in Raf/MAPK pathway
              4.3.9 Kinases in PI3K/Akt pathway
              4.3.10 Kinases in NF-B pathway
              4.3.11 Kinases in JNK/SAPK pathway
              4.3.12 Src family
              4.3.13 Aurora family
              4.3.14 Other kinase targets

           4.4 Tyrosine phosphatases

           4.5 Kinase profiling of cancers

         CHAPTER 5 PROTEIN KINASE TARGETS IN OTHER DISEASES

           5.1 Inflammation and tissue injury
              5.1.1 Introduction
                5.1.1.1 Current treatments
              5.1.2 Kinase targets
                5.1.2.1 p38 MAPK
                5.1.2.2 JNKs
                5.1.2.3 IKK
                5.1.2.4 Other kinase targets
              5.1.3 Phosphatase targets

           5.2 Diabetes and insulin resistance
              5.2.1 Introduction
              5.2.2 Current treatments
              5.2.3 Involvement of stress pathways
              5.2.4 Kinase targets
                5.2.4.1 PKC-beta and VEGFR
                5.2.4.2 c-raf
                5.2.4.3 Insulin receptor
                5.2.4.4 GSK-3
                5.2.4.5 GRK
              5.2.5 Phosphatase targets

           5.3 Neurological diseases and stroke
              5.3.1 Introduction
              5.3.2 Kinase targets
                5.3.2.1 Kinases in JNK/SAPK pathway
                5.3.2.2 CK-1
                5.3.2.3 GSK-3beta
                5.3.2.4 p38 MAPK

           5.4 Osteoporosis and related bone diseases
              5.4.1 Introduction
              5.4.2 Src kinase

           5.5 Other diseases
              5.5.1 Septic shock
              5.5.2 Bacterial infections
              5.5.3 Viral infections
              5.5.4 Macular degeneration
              5.5.5 Cardiac hypertrophy

           5.6 New directions

         CHAPTER 6  MARKET CONSIDERATIONS AND FORECASTS

           6.1 Overview of the major markets
              6.1.1 Global population growth
              6.1.2 The US healthcare market
              6.1.3 The Japanese healthcare market
              6.1.4 The European healthcare markets
                6.1.4.1 Germany
                6.1.4.2 France
                6.1.4.3 Italy
                6.1.4.4 United Kingdom
                6.1.4.5 Spain
              6.1.5 Emerging markets
              6.1.6 Growth of pharma markets in 2002

           6.2 Market forecasts by disease
              6.2.1 Prevalence of targeted diseases
              6.2.2 Cancer
                6.2.2.1 The existing drug market
                6.2.2.2 Market forecasts for kinase inhibitors
                  6.2.2.2.1 EGFR inhibitors
                  6.2.2.2.2 Protein kinases in hematologic
                            malignancies
                  6.2.2.2.3 Angiogenic kinase receptors
                  6.2.2.2.4 PKC family
                  6.2.2.2.5 Other kinase targets
              6.2.3 Inflammatory disorders
                6.2.3.1 The existing market
                6.2.3.2 Market forecasts for kinase inhibitors
              6.2.4 Diabetic microvascular complications

           6.3 Market forecasts by geographical region

           6.4 Leading players

         CHAPTER 7 COMPANY PROFILES

           7.1  Amgen Inc
           7.2  ARIAD Pharmaceuticals Inc
           7.3  ArQule Inc
           7.4  AstraZeneca Plc
           7.5  Axxima Pharmaceuticals AG
           7.6  Biofocus plc
           7.7  Celgene Corporation
           7.8  Cellular Genomics Inc
           7.9  Cephalon Inc
           7.10  Eli Lilly and Co
           7.11  eXegenics Inc
           7.12  Genentech Inc
           7.13  GlaxoSmithKline plc
           7.14  Hybridon Inc
           7.15  ICOS Corporation
           7.16  ImClone Systems Inc
           7.17  Incyte Corporation
           7.18  Isis Pharmaceuticals Inc
           7.19  Keryx Biopharmaceuticals Inc
           7.20  Nanogen Inc
           7.21  Novartis Pharma AG
           7.22  Onyx Pharmaceuticals Inc
           7.23  OSI Pharmaceuticals
           7.24  Pfizer Inc
           7.25  Scios Inc
           7.26  Sirna Therapeutics Inc
           7.27  Structural GenomiX
           7.28  Syrrx Inc
           7.29  Telik Inc
           7.30  Vertex Pharmaceuticals Inc

         CHAPTER 8 TRENDS AND OPPORTUNITIES

           8.1 The druggable kinase superfamily
           8.2 Low toxicity agents
           8.3 Young biotech companies driving innovation
           8.4 Improving ATP-competitive inhibitors
           8.5 Beyond ATP-competitive inhibition
           8.6 Targeting the kinase activation site
           8.7 Targeting kinase-substrate interactions
           8.8 Future alternatives to small molecule drugs
           8.9 Leukemias: market uptake regardless of price
           8.10 Solid tumors: lessons learnt
           8.11 Surrogate biomarkers: role in trials
           8.12 Resistance creates commercial opportunities
           8.13 Theranostic tests: key to therapy success
           8.14 Towards kinase-based tumor profiling
           8.15 Targeting activation profiles
           8.16 Targeting splice variants
           8.17 First kinase activators
           8.18 Inflammation: challenge to biologics
           8.19 Diabetes: many promising approaches
           8.20 Extending the range of clinical indications
           8.21 Unexplored kinase targets in cancer
           8.22 Unexplored kinase targets in other diseases

EXECUTIVE SUMMARY
Protein kinases play a central role in diverse signal transduction pathways involved in the control of cell growth, metabolism, differentiation, and apoptosis. The 518 human protein kinase genes which were identified in 2002 offer a bewildering choice of potential kinase targets.
Although this is nascent market, the first two widely launched agents, Genentech's Herceptin and Novartis' Gleevec, have already achieved combined sales of $1 billion in 2002. We are forecasting sales of $4.6 billion for 2007, mainly in the therapeutic area of cancer.
Beginning with an overview of the kinase family and the signaling pathways in which kinases play a key role, this report comprehensively reviews and assesses kinase targets currently under commercial investigation, and highlights unexplored areas of opportunity. The scope is wide, covering small molecule, monoclonal antibody, antisense and RNA-based kinase inhibitors under commercial development for a broad range of clinical indications. Although most endeavour is currently directed at the development of kinase inhibitors, kinase activation is also of potential importance, and developments in this area are included.
Kinase inhibitors under commercial development are directed at extracellular as well as intracellular kinase targets. Most agents target the kinase catalytic domain. We report on ongoing efforts to improve traditional ATP competitive inhibitors and develop alternative approaches to inhibition of kinase catalytic function. We also review traditional agents targeting extracellular ligand- binding kinase domains, as well as newer agents targeting kinase activation domains and substrate binding domains.
Proteomic technologies are enabling rational drug design, providing new insights into conformational variability between kinases, and expanding our understanding of the role of kinases in health and disease.
The rate of drug discovery in this area is set to accelerate. This is likely to be enabled by the growing trend to direct the early portion of the drug discovery process toward target gene families, rather than therapeutic areas. We review curent trends in kinase drug discovery, highlight promising proprietary approaches to target identification, target validation, lead generation, and lead optimization, and identify issues of special relevance to kinase drug discovery, such as inhibitor specificity, surrogate biomarkers, and substrate identification.
Protein kinase genes are commonly mutated or dysregulated in cancer, and as a result rationally designed kinase inhibitors are set to be major players in the next generation of targeted cancer therapies. The trailblazing targeted anti-cancer kinase inhibitors Herceptin and Gleevec have given the world a foretaste of personalized medicine of the future. We review kinases which have been considered prime targets for the development of selective inhibitors - the epidermal growthfactor receptor kinase family, kinases involved in hematologic malignancies, kinases involved in the neo- vascularization of tumors, the protein kinase C family, and the cell cycle regulating kinases. The range of kinase targets has been steadily expanded to include other kinase families believed to play an important part in the etiology of cancer. We comment on positive findings as well as setbacks encountered and highlight areas of opportunity.
Outside the cancer field, blockbuster potential resides in kinase- targeting drugs in late stages of clinical development for the treatment of inflammatory diseases and for the treatment of diabetic microvascular complications. In rheumatoidarthritis, potential challenge to injectable biologics comes in the form of orally active small molecule inhibitors of p38 kinase. Protein kinase C-targeting inhibitors in clinical trials address the causes of diabetic retinopathy, for which no treatments currently exist. Promising agents for treating insulin resistance associated with type 2 diabetes are also under investigation.
The range of clinical indications for kinase inhibitors is being extended with preclinical studies and early stage clinical trials addressing diseases as diverse as neurodegenerative diseases, osteoporosis, macular degeneration, septic shock, bacterial infections, and viral infections.
Despite the progress so far, many promising targets in cancer and other diseases remain unexplored. In 2002, the Human Kinome Project (HKP) published findings which revealed that 164 kinases map to cancer loci and a further 80 kinases map to loci implicated in other diseases. Many of those potential kinase targets in cancer have yet to be explored. Likewise, important non-malignant conditions associated with specific kinases identified by the HKP are not currently a major focus of investigation.
The report profiles 30 key companies active in the kinase drug discovery, which includes small specialist companies, commercial- stage biotech companies, and large pharmaceutical companies. Information is provided on recent acquisitions and collaborations in this area. Although the report is focused on protein kinases, company profiles also contain information on drugs targeting protein phosphatases, which despite their potential importance, are currently few in number.