Kinases: Advanced Strategies and Multiple Targets for Drug Discovery (2nd Edn).

Kinases: Advanced Strategies and Multiple Targets for Drug Discovery (2nd Edn).

Publisher:	D&MD Publications Inc
Year of publication:	2006
Type of publication:	Management report
Publisher's reference (if any):	D&MD9217
Author(s):	Sreten Bogdanovic and Beata Langlands
Approximate page count:	350
Price when published:	$5,275
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.
KINASES Advanced Strategies and Multiple Targets for Drug Discovery (2nd Edn). TABLE OF CONTENTS EXECUTIVE SUMMARY CHAPTER 1 WHY TARGET KINASES? 1.1 Introduction 1.2 Overview of human protein kinases 1.2.1 Classification schemes 1.3 Kinases in signal transduction pathways 1.3.1 MAP kinase pathways 1.3.1.1 MAPK (ERK) pathway 1.3.1.2 JNK/SAPK pathway 1.3.1.3 p38 MAPK pathway 1.3.2 PI3K/Akt signaling 1.3.3 Jak/STAT signaling 1.3.3.1 Jak/STAT3 signaling in cancer 1.3.4 Insulin Receptor Signaling 1.3.5 NF-B pathway 1.3.5.1 TNF signaling in cancer 1.3.6 Immune cell signaling 1.3.6.1 T Cell Receptor signaling 1.3.6.2 B-Cell Receptor Complexes 1.3.7 Signaling in vascular morphogenesis 1.3.7.1 VEGF receptor signaling 1.3.8 EGF receptor signaling 1.3.9 Cyclic nucleotide metabolism 1.3.10 Cell cycle checkpoint controls 1.4 Categories of kinase-targeted drugs 1.4.1 Small molecules 1.4.2. Biopharmaceuticals 1.5 Survey of kinase inhibitors under development 1.5.1 Developing companies 1.5.2 Indications 1.5.3 Targets 1.5.4 Categories (origin of material) CHAPTER 2 FOCUS ON SMALL MOLECULE KINASE INHIBITORS 2.1 Introduction 2.1.1 Mechanisms of kinase inhibition 2.2 The kinase drug discovery process 2.2.1 Improving target validation 2.2.1.1 Use of RNAi and aptamers 2.2.2 Improving HTS processes 2.2.3 Improving structure-based drug design 2.2.4 Monitoring kinase activity 2.2.4.1 Primary screens 2.2.4.2 Secondary screens 2.2.4.3 Cell-based assays 2.3 Identifying substrates of novel kinases 2.3.1 In vitro and in vivo assays 2.3.2 Use of peptide libraries 2.3.3 Use of protein microarrays CHAPTER 3 KINASE TARGETS IN CANCER 3.1 Introduction 3.2 Overview of cancer 3.2.1 Established therapies 3.2.2 Molecular targeted therapies 3.3 Kinases in cancer 3.3.1 Kinase profiling of individual tumors 3.4 Inhibiting multiple cancer-related kinases 3.4.1 FDA approved multi-target kinase inhibitors 3.5 Protein kinases as drug targets 3.6 TK Group 3.6.1 Abl Family 3.6.1.1 Gleevec (imatinib) 3.6.1.2 Sprycel (dasatinib) 3.6.1.3 Nilotinib 3.6.2 EGFR Family 3.6.2.1 Herceptin (trastuzumab) 3.6.2.2 Erbitux (cetuximab) 3.6.2.3 Iressa (gefitinib) 3.6.2.4 Tarceva (erlotinib) 3.6.2.5 Lapatinib 3.6.3 Eph Family 3.6.4 FGFR Family 3.6.5 VEGFR Family 3.6.6 PDGFR Family 3.6.7 Src Family 3.6.8 Ret Family 3.6.9 Trk Family 3.7 TKL Group 3.7.1 RAF Family 3.8 AGC Group 3.8.1 AKT Family 3.8.2 PKC Family 3.9 CMGC Group 3.9.1 CDK Family 3.9.2 MAPK Family 3.10 STE Group 3.11 "Other" Group 3.11.1 Aurora family 3.12 Atypical Group 3.13 Dual specificity lipid/protein kinases CHAPTER 4 PROTEIN KINASE TARGETS IN OTHER DISEASES 4.1 Introduction 4.2 Inflammation and tissue injury 4.2.1 Background 4.2.1.1 Current treatments 4.2.2 Kinase targets 4.2.2.1 MAPK14 4.2.2.2 PRKCA 4.2.2.3 FRAP1 4.3 Diabetes and insulin resistance 4.3.1 Background 4.3.1.1 Current treatments 4.3.2 Kinase targets 4.3.2.1 Kinase targets of metformin 4.3.2.2 GSK3B 4.3.2.3 PRKCB1 4.3.2.4 KDR 4.3.2.5 GCK 4.4 Cardiovascular disease 4.4.1 Background 4.4.1.1 Percutaneous coronary interventions 4.4.2 Kinase targets 4.4.2.1 FRAP1 4.4.2.2 PDGFRA 4.4.2.3 MAPK14 4.5 Other applications CHAPTER 5 STAKING CLAIMS TO THE HUMAN KINOME 5.1 Introduction 5.2 Overview of Patents 5.3 Role of patents in the biomedical industry 5.4 Patenting of genes and proteins 5.5 The kinase patent data set 5.6 Kinase Patent Activities 5.7 Forward citations 5.8 Patent assignees CHAPTER 6 MARKET CONSIDERATIONS AND FORECASTS 6.1 Introduction 6.2 The Survey 6.2.1 Preliminary remarks 6.2.2 Questions and answers 6.2.3 Conclusions 6.3 Kinase Drug R&D: Leading Indications 6.4 Kinase Drug R&D: Leading Companies 6.5 Kinase Drug R&D: Leading Targets 6.6 Kinase Drug Companies, Indications, and Targets 6.7 The World Pharmaceutical Market 6.8 Kinase markets 6.8.1 Cancer 6.8.1.1 Hematologic cancers 6.8.1.2 Solid tumors 6.8.2 Diabetes 6.8.3 Inflammation and tissue injury 6.8.4 Cardiovascular disease 6.8.5 Central Nervous System 6.9 Market Analysis and Forecasts 6.9.1 Cancer 6.9.2 Diabetes 6.9.3 Immunology/Inflammation 6.9.4 Cardiology 6.9.5 Central Nervous System 6.9.6 Geographical markets CHAPTER 7 TRENDS AND OPPORTUNITIES 7.1 Kinases: the big picture 7.2 Actual and potential targets of kinase drugs 7.3 Checking the commercial pulse 7.4 A revolution in cancer treatment 7.5 Drug resistance: a pressing problem 7.6 Single versus multiple target debate EXECUTIVE SUMMARY During the last five years, eight anticancer kinase inhibitors received FDA approval, increasing recognition of kinases as an important class of drug targets. In order to comprehensively assess the scientific, clinical, and commercial progress and prospects in this field, the following surveys were carried out exclusively for this report: a search of Pharmaprojects, the leading database tracking pharmaceutical R&D worldwide; a survey of the last six years of kinase-related patenting at the US PTO; and an on-line survey of pharmaceutical industry and academic personnel. We forecast that the kinase-targeted drug market will grow from $12.7 billion in 2005 to $58.6 billion in 2010. Cancer (mainly solid tumors) will remain the dominant application throughout the forecast period. Reversible protein phosphorylation, catalyzed by kinases, is a ubiquitous mechanism for the control of signal transduction networks that regulate many vital biological processes. Cancer and other proliferation-related disorders are associated with stimulation of intra-cellular signaling, and since kinases (most of the time) positively relay signaling events, their inhibition offers a powerful way to block aberrant signal transduction cascades. The focus throughout this report is on inhibitors of protein kinases, although, where appropriate, protein kinase stimulators are also discussed, as are modulators of lipid and sugar kinases. The search of the Pharmaprojects database generated 803 drug profiles representing 243 unique companies, 184 unique targets, and 68 unique indications/drug types. A subsequent search of the Entrez Gene database for human genes with kinase activity led us to conclude that (according to Pharmaprojects) 145 kinase-related genes are currently drug targets, while 627 kinase-related genes remain unexplored as drug targets. Examination of the Pharmaprojects dataset revealed that the kinase drug market is at an early stage; overall 80% of drugs are still in preclinical development. By far the largest indication for kinase-targeted drugs, almost 41% of the total, is cancer. Of the top five kinase drug targets, only one is not primarily a cancer target. Other important indications for kinase-targeted drugs include inflammation, arthritis, diabetes, and cardiovascular disease. Of the top ten companies most active in this area, only Pfizer, Novartis, AstraZeneca, and GlaxoSmithKline have launched products. Currently, the emphasis is on small molecule approaches to kinase inhibition. The majority of the respondents to our on-line survey felt that small molecule inhibitors were preferable to monoclonal antibodies and that multi-target kinase inhibitors were more likely to prove commercially successful that single-target inhibitors. Now that many kinases have been sequenced and their structures have been determined, more efficient approaches to small molecule kinase inhibitor discovery are urgently needed. We discuss recent advances in this area, with a particular focus on the development of newassays for use in high throughput screening for potential inhibitors, specificity profiling of candidate drugs, and identifying physiological substrates of targeted kinases. Despite the current focus on small molecule inhibitors, the industry appears to be moving towards a more balanced portfolio of small molecules and biopharmaceuticals. According to Pharmaprojects, more than 20% of kinase-targeted drugs in development, especially those addressing cancer, are biopharmaceuticals. Our patent search identified 3,687 kinase-related US patents and patent applications filed since January 2000 and revealed that they are being filed at a steady rate of around 730 per year. Amongst other findings, the data on patented materials suggest that many more innovative biotherapeutics targeting kinases can be expected over the next 10-15 years. We review established and emerging kinase drug targets in cancer and the status and nature of drugs directed at them. A large proportion of late-stage clinical trials target receptor tyrosine kinases. The discovery of activating and resistance mutations has fueled the drive towards mutation-specific therapies that could provide patients with a drug that matches the genetic profile of their biopsied tumor. While some companies endeavour to design highly selective single-target inhibitors, others are developing multi-target kinase inhibitors. Companies betting on the latter approach can screen drugs for desirable effects on cancer processes such as proliferation or angiogenesis which are mediated by kinases frequently mutated or overexpressed in tumors, without investing heavily in the technologies needed to develop highly selective drugs. Outside of cancer, the only launched drugs are agents which were not developed with kinase modulation in mind, but are now known to affect disease-associated kinases. Although kinase-targeted drugs are currently under investigation for over 50 unique indications, most commercial activity centres in the areas of inflammation and tissue injury, diabetes and cardiovascular disease. We review the progress that is being made in these areas, the major kinase drug targets and the status and nature of drugs directed at them.

EXECUTIVE SUMMARY
During the last five years, eight anticancer kinase inhibitors received FDA approval, increasing recognition of kinases as an important class of drug targets. In order to comprehensively assess the scientific, clinical, and commercial progress and prospects in this field, the following surveys were carried out exclusively for this report: a search of Pharmaprojects, the leading database tracking pharmaceutical R&D worldwide; a survey of the last six years of kinase-related patenting at the US PTO; and an on-line survey of pharmaceutical industry and academic personnel.
We forecast that the kinase-targeted drug market will grow from $12.7 billion in 2005 to $58.6 billion in 2010. Cancer (mainly solid tumors) will remain the dominant application throughout the forecast period.
Reversible protein phosphorylation, catalyzed by kinases, is a ubiquitous mechanism for the control of signal transduction networks that regulate many vital biological processes. Cancer and other proliferation-related disorders are associated with stimulation of intra-cellular signaling, and since kinases (most of the time) positively relay signaling events, their inhibition offers a powerful way to block aberrant signal transduction cascades. The focus throughout this report is on inhibitors of protein kinases, although, where appropriate, protein kinase stimulators are also discussed, as are modulators of lipid and sugar kinases.
The search of the Pharmaprojects database generated 803 drug profiles representing 243 unique companies, 184 unique targets, and 68 unique indications/drug types. A subsequent search of the Entrez Gene database for human genes with kinase activity led us to conclude that (according to Pharmaprojects) 145 kinase-related genes are currently drug targets, while 627 kinase-related genes remain unexplored as drug targets.
Examination of the Pharmaprojects dataset revealed that the kinase drug market is at an early stage; overall 80% of drugs are still in preclinical development. By far the largest indication for kinase-targeted drugs, almost 41% of the total, is cancer. Of the top five kinase drug targets, only one is not primarily a cancer target. Other important indications for kinase-targeted drugs include inflammation, arthritis, diabetes, and cardiovascular disease. Of the top ten companies most active in this area, only Pfizer, Novartis, AstraZeneca, and GlaxoSmithKline have launched products.
Currently, the emphasis is on small molecule approaches to kinase inhibition. The majority of the respondents to our on-line survey felt that small molecule inhibitors were preferable to monoclonal antibodies and that multi-target kinase inhibitors were more likely to prove commercially successful that single-target inhibitors. Now that many kinases have been sequenced and their structures have been determined, more efficient approaches to small molecule kinase inhibitor discovery are urgently needed. We discuss recent advances in this area, with a particular focus on the development of newassays for use in high throughput screening for potential inhibitors, specificity profiling of candidate drugs, and identifying physiological substrates of targeted kinases.
Despite the current focus on small molecule inhibitors, the industry appears to be moving towards a more balanced portfolio of small molecules and biopharmaceuticals. According to Pharmaprojects, more than 20% of kinase-targeted drugs in development, especially those addressing cancer, are biopharmaceuticals. Our patent search identified 3,687 kinase-related US patents and patent applications filed since January 2000 and revealed that they are being filed at a steady rate of around 730 per year. Amongst other findings, the data on patented materials suggest that many more innovative biotherapeutics targeting kinases can be expected over the next 10-15 years.
We review established and emerging kinase drug targets in cancer and the status and nature of drugs directed at them. A large proportion of late-stage clinical trials target receptor tyrosine kinases. The discovery of activating and resistance mutations has fueled the drive towards mutation-specific therapies that could provide patients with a drug that matches the genetic profile of their biopsied tumor. While some companies endeavour to design highly selective single-target inhibitors, others are developing multi-target kinase inhibitors. Companies betting on the latter approach can screen drugs for desirable effects on cancer processes such as proliferation or angiogenesis which are mediated by kinases frequently mutated or overexpressed in tumors, without investing heavily in the technologies needed to develop highly selective drugs.
Outside of cancer, the only launched drugs are agents which were not developed with kinase modulation in mind, but are now known to affect disease-associated kinases. Although kinase-targeted drugs are currently under investigation for over 50 unique indications, most commercial activity centres in the areas of inflammation and tissue injury, diabetes and cardiovascular disease. We review the progress that is being made in these areas, the major kinase drug targets and the status and nature of drugs directed at them.