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Executive Summary

   Chapter 1 Kinases as drug targets
   Chapter 2 Small molecule kinase inhibitor discovery
   Chapter 3 Targeting kinases in cancer
   Chapter 4 Non-cancer applications of kinase drugs
   Chapter 5 Leading kinase drug originating companies
   Chapter 6 Market Analysis: Trends and Forecasts

Chapter 1  Kinases as Drug Targets

  1.0 Executive summary
  1.1 Introduction
     1.2.1 Overview of human protein kinases
       1.2.1.1 Classification schemes
  1.3 Kinases in signal transduction pathways
     1.3.1 MAPK pathways
       1.3.1.1 MAPK (ERK) pathway
       1.3.1.2 JNK/SAPK pathway
       1.3.1.3 MAPK14 pathway
     1.3.2 PI3K/AKT signaling
     1.3.3 JAK/STAT signaling
     1.3.4 NFKB pathway
     1.3.5 Insulin receptor signaling
     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 Monoclonal antibodies
     1.4.3 Emerging biopharmaceuticals
  1.5 Kinase drug audit

Chapter 2  Small molecule kinase inhibitor discovery

  2.0 Executive summary
  2.1 Introduction
  2.2 Mechanisms of kinase inhibition
     2.2.1 ATP competitive inhibitors
     2.2.2 Irreversible inhibitors
     2.2.3 Allosteric inhibitors
  2.3 Approaches to kinase inhibitor discovery
     2.3.1 Traditional kinase inhibitor discovery
       2.3.1.1 HS screening of compound libraries
       2.3.1.2 Lead optimization
     2.3.2 Synthesis of inhibitor analogs
     2.3.3 Structure-informed drug design
       2.3.3.1 Structure-informed drug re-design
     2.3.4 Fragment-based drug discovery
  2.4 Kinase inhibitor selectivity assays
     2.4.1 Protein selectivity assays
       2.4.1.1 Kinase activity assays
       2.4.1.2 Kinase binding assays
     2.4.2 Cellular selectivity assays
  2.5 Identifying substrates of kinases

Chapter 3  Targeting kinases in cancer

  3.0 Executive summary
  3.1 Overview of cancer
  3.2 Established and emerging therapies
  3.3 Therapeutic potential of kinase inhibition
     3.3.1 Types of kinase targets
       3.3.1.1 Mutationally-activated kinases
       3.3.1.2 Kinases which sustain tumor growth
       3.3.1.3 Kinases with roles in tumorigenesis
  3.4 Top 20 kinase targets
  3.5 Group: TK
     3.5.1 ABL1 (Abl family)
       3.5.1.1 Target characteristics
       3.5.1.2 Inhibitors on the market
       3.5.1.3 Inhibitors in development
     3.5.2 EGFR and ERBB2 (EGFR family)
       3.5.2.1 Target characteristics
       3.5.2.2 Approaches to EGFR inhibition
       3.5.2.3 Inhibitors on the market
       3.5.2.4 Inhibitors in development
     3.5.3 FLT3, KIT, PDGFRA, and PDGFRB (PDGFR family)
       3.5.3.1 Target characteristics
       3.5.3.2 Inhibitors on the market
       3.5.3.3 Inhibitors in development
     3.5.4 FLT1, FLT4, and KDR (VEGFR family)
       3.5.4.1 Target characteristics
       3.5.4.2 Inhibitors on the market
       3.5.4.3 Inhibitors in development
     3.5.5 JAK2 (JakA family)
       3.5.5.1 Target characteristics
       3.5.5.2 Drugs in development
     3.5.6 MET (Met family)
       3.5.6.1 Target characteristics
       3.5.6.2 Agents in development
  3.6 Group: AGC
     3.6.1 AKT1 (AKT family)
       3.6.1.1 Target characteristics
       3.6.1.2 Drugs in development
  3.7 Group: CMGC
     3.7.1 CDC2 and CDK2 (CDK family; CDC2 subfamily)
       3.7.1.1 Target characteristics
       3.7.1.2 Drugs in development
  3.8 Group: Other
     3.8.1 AURKA and AURKB (AUR family)
       3.8.1.1 Target characteristics
       3.8.1.2 Drugs in development
     3.8.2 PLK1 (PLK family)
       3.8.2.1 Target characteristics
       3.8.2.2 Drugs in development
  3.9 Group: Atypical
     3.9.1 FRAP1 (PIKK family, FRAP subfamily)
       3.9.1.1 Target characteristics
       3.9.1.2 Inhibitors on the market
       3.9.1.3 Inhibitors in development
  3.10 Dual specificity lipid/protein kinases
     3.10.1 PIK3CA (PI3K)
       3.10.1.1 Target characteristics
       3.10.1.2 Inhibitors in development
  3.11 Future trends

Chapter 4  Non-cancer applications of kinase drugs

  4.0 Executive summary
  4.1 Introduction
  4.2 Chronic inflammation and kinases
  4.3 Leading indications
       4.3.1 Arthritis
       4.3.2 Diabetes
       4.3.3 Inflammation
       4.3.4 Immunosuppression
       4.3.5 Ophthalmology
       4.3.6 Psoriasis
       4.3.7 Pulmonary
       4.3.8 Cardiovascular
       4.3.9 Myelodysplastic disorders
       4.3.10 GI disorders
       4.3.11 Pain
  4.4 Leading kinase targets
     4.4.1 MAPK14
       4.4.1.1 Target characteristics
       4.4.1.2 Inhibitors in development
     4.4.2 FRAP1
       4.4.2.1 Target characteristics
       4.4.2.2 Inhibitors on the market
       4.4.2.3 Inhibitors in development
     4.4.3 JAK3
       4.4.3.1 Target characteristics
       4.4.3.2 Inhibitors in development
     4.4.4 NTRK1
       4.4.4.1 Target characteristics
       4.4.4.2 Inhibitors in development
     4.4.5 ROCK1
       4.4.5.1 Target characteristics
       4.4.5.2 Inhibitors on the market
       4.4.5.3 Inhibitors in development

Chapter 5  Leading kinase drug originating companies

  5.0 Executive summary/Introduction
  5.1 Abbott Laboratories
     5.1.1 Company overview
     5.1.2 Kinase-related collaborations (2005 onwards)
     5.1.3 Kinase drug pipeline
  5.2 Ambit Biosciences Corp
     5.2.1 Company overview
     5.2.2 Kinase-related collaborations (2005 onwards)
     5.2.3 Kinase drug pipeline
  5.3 Amgen Inc
     5.3.1 Company overview
     5.3.2 Kinase-related collaborations (2005 onwards)
     5.3.3 Kinase drug pipeline
  5.4 Array BioPharma Inc
     5.4.1 Company overview
     5.4.2 Kinase-related collaborations (2005 onwards)
     5.4.3 Kinase drug pipeline
  5.5 AstraZeneca plc
     5.5.1 Company overview
     5.5.2 Kinase-related collaborations (2005 onwards)
     5.5.3 Kinase drug pipeline
  5.6 Avila Therapeutics Inc
     5.6.1 Company overview
     5.6.2 Kinase drug pipeline
  5.7 Boehringer Ingelheim GmbH
     5.7.1 Company overview
     5.7.2 Kinase-related collaborations (2005 onwards)
     5.7.3 Kinase drug pipeline
  5.8 Bristol-Myers Squibb Co
     5.8.1 Company overview
     5.8.2 Kinase-related collaborations (2005 onwards)
     5.8.3 Kinase drug pipeline
  5.9 Cephalon Inc
     5.9.1 Company overview
     5.9.2 Kinase-related collaborations (2005 onwards)
     5.9.3 Kinase drug pipeline
  5.10 Deciphera Pharmaceuticals LLC
     5.10.1 Company overview
     5.10.2 Kinase-related collaborations (2005 onwards)
     5.10.3 Kinase drug pipeline
  5.11 Eli Lilly Co
     5.11.1 Company overview
     5.11.2 Kinase-related collaborations (2005 onwards)
     5.11.3 Kinase drug pipeline
  5.12 Exelixis Inc
     5.12.1 Company overview
     5.12.2 Kinase-related collaborations (2005 onwards)
     5.12.3 Kinase drug pipeline
  5.13 GlaxoSmithKline plc
     5.13.1 Company overview
     5.13.2 Kinase-related collaborations (2005 onwards)
     5.13.3 Kinase drug pipeline
  5.14 Hoffmann-La Roche Ltd (subsidiary Genentech)
     5.14.1 Company overview
     5.14.2 Kinase-related collaborations (2005 onwards)
     5.14.3 Kinase drug pipeline
  5.15 Johnson & Johnson
     5.15.1 Company overview
     5.15.2 Kinase-related collaborations (2005 onwards)
     5.15.3 Kinase drug pipeline
  5.16 Kyowa Hakko Kirin Co Ltd
     5.16.1 Company overview
     5.16.2 Kinase-related collaborations (2005 onwards)
     5.16.3 Kinase drug pipeline
  5.17 Novartis International AG
     5.17.1 Company overview
     5.17.2 Kinase-related collaborations (2005 onwards)
     5.17.3 Kinase drug pipeline
  5.18 Pfizer Inc
     5.18.1 Company overview
     5.18.2 Kinase-related collaborations (2005 onwards)
     5.18.3 Kinase drug pipeline
  5.19 Sanofi-Aventis Group
     5.19.1 Company overview
     5.19.2 Kinase drug pipeline
  5.20 Wyeth
     5.20.1 Company overview
     5.20.2 Kinase-related collaborations (2005 onwards)
     5.20.3 Kinase drug pipeline

Chapter 6  Market Analysis: Trends and Forecasts

  6.0 Chapter Summary
  6.1 Prevalence of targeted diseases
  6.2 Analyses and Forecasts by Type of Agent
     6.2.1 Limus agents/mTOR inhibitors
       6.2.1.1 Overview
       6.2.1.2 Standalone mTOR inhibitors
       6.2.1.3 Drug-eluting stents
       6.2.1.4 Drug-eluting stent market
       6.2.1.5 Sirolimus-eluting stents
       6.2.1.6 Everolimus- and zotarolimus-eluting stents
       6.2.1.7 Sales trends in mTOR inhibitors
       6.2.1.8 Forthcoming mTOR inhibitors
     6.2.2 EGFR Family inhibitors
       6.2.2.1 Overview
       6.2.2.2 Trastuzumab
       6.2.2.3 Erlotinib
       6.2.2.4 Cetuximab
       6.2.2.5 Gefitinib
       6.2.2.6 Panitumumab
       6.2.2.7 Lapatinib
       6.2.2.8 Nimotuzumab
       6.2.2.8 Sales trends in EGFR Family inhibitors
       6.2.2.9 Forthcoming EGFR Family Inhibitors
     6.2.3 ABL/FLT3 Group Inhibitors
       6.2.3.1 Overview
       6.2.3.2 Imatinib
       6.2.3.3 Dasatinib
       6.2.3.4 Nilotinib
       6.2.3.5 Sales trends in ABL1/FLT3 Family Inhibitors
       6.2.3.6 Forthcoming ABL1/FLT3 Family Inhibitors
     6.2.4 VEGFR Family
       6.2.4.1 Overview
       6.2.4.2 Sunitinib
       6.2.4.3 Sorafenib
       6.2.4.4 Sales trends in VEGFR Family inhibitors
       6.2.4.5 Forthcoming VEGFR Family Inhibitors
     6.2.5 Other launched agents
       6.2.5.1 Overview
       6.2.5.2 Fasudil
       6.2.5.3 Pirfenidone
       6.2.5.4 Sales trends in other agents
       6.2.5.5 Other forthcoming agents
  6.3 Company Sales and Trends
  6.4 Patenting Trends

Appendix 1	Kinase-related targets and their abbreviations
Appendix 2	Other abbreviations and acronyms
Appendix 3	Research Methodology

List of Figures

   Figure 1.1	Kinase Target Landscape
   Figure 6.1	Kinase Originator Market Shares

List of Tables

   Table 1.1	Human Kinase Gene Audit
   Table 1.2	Hanks Classification of Protein Kinases (1995)
   Table 1.3	Human Kinase Group and Family Relationships
   Table 1.4	Kinase Agents By Development Stage
   Table 1.5	Kinase Drugs By Product Type
   Table 1.6	Leading Kinase-targeted Drug Applications
   Table 1.7	Kinase Agents By Indication
   Table 1.8	Kinase Agents By Originator
   Table 1.9	Kinase Agents By Target
   Table 1.10	Kinase Agonists and Stimulants
   Table 3.1	Associations of Human Protein Kinases with Cancer Amplicons
   Table 3.2	Kinases implicated in human cancer
   Table 3.3	Overview of Cancer-Related Kinase Agents by Status
   Table 3.4	Cancer-related Kinase Targets By Most Advanced Development Stage
   Table 3.5	Top 20 Kinase Targets In Cancer
   Table 3.6	Group, Family, and Subfamily Assignments of the main Protein Kinase Targets in Cancer
   Table 3.7	Overview of ABL1-Targeted Agents in Cancer
   Table 3.8	Overview of EGFR-Targeted Agents in Cancer
   Table 3.9	Overview of ERBB2-Targeted Agents in Cancer
   Table 3.10	Overview of FLT3-Targeted Agents in Cancer
   Table 3.11	Overview of KIT-Targeted Agents in Cancer
   Table 3.12	Overview of PDGFRA-Targeted Agents in Cancer
   Table 3.13	Overview of PDGFRB-Targeted Agents in Cancer
   Table 3.14	Overview of FLT1-Targeted Agents in Cancer
   Table 3.15	Overview of FLT4-Targeted Agents in Cancer
   Table 3.16	Overview of KDR-Targeted Agents in Cancer
   Table 3.17	Overview of JAK2-Targeted Agents in Cancer
   Table 3.18	Overview of MET-Targeted Agents in Cancer
   Table 3.19	Overview of AKT1-Targeted Agents in Cancer
   Table 3.20	Overview of CDC2-Targeted Agents in Cancer
   Table 3.21	Overview of CDK2-Targeted Agents in Cancer
   Table 3.22	Overview of AURKA-Targeted Agents in Cancer
   Table 3.23	Overview of AURKB-Targeted Agents in Cancer
   Table 3.24	Overview of PLK1-Targeted Agents in Cancer
   Table 3.25	Overview of FRAP1-Targeted Agents in Cancer
   Table 3.26	Overview of PIK3CA-Targeted Agents in Cancer
   Table 3.27	Overview of Cancer-Related Kinase Agents by Target
   Table 4.1	Overview of Non-Cancer Kinase Agents by Status
   Table 4.2	Non Cancer-related Kinase Targets By Most Advanced Development Stage
   Table 4.3	Kinase-Targeted Agents With Anti-Arthritic Applications
   Table 4.4	Kinase-Targeted Agents With Diabetes Applications
   Table 4.5	Kinase-Targeted Agents With Inflammatory Applications
   Table 4.6	Kinase-Targeted Agents With Immunosuppressive Applications
   Table 4.7	Kinase-Targeted Agents With Ophthalmological Applications
   Table 4.8	Kinase-Targeted Agents With Psoriasis Applications
   Table 4.9	Kinase-Targeted Agents With Pulmonary Applications
   Table 4.10	Kinase-Targeted Agents With Cardiovascular Applications
   Table 4.11	Kinase-Targeted Agents With Myelodysplastic Applications
   Table 4.12	Kinase-Targeted Agents With GI Applications
   Table 4.13	Kinase-Targeted Agents With Pain Applications
   Table 5.1	Overview of Abbott's Kinase Pipeline by Status
   Table 5.2	Overview of Ambit Biosciences' Kinase Pipeline by Status
   Table 5.3	Overview of Amgen's Kinase Pipeline by Status
   Table 5.4	Overview of Array BioPharma's Kinase Pipeline by Status
   Table 5.5	Overview of AstraZeneca's Kinase Pipeline by Status
   Table 5.6	Overview of Avila Therapeutics' Kinase Pipeline by Status
   Table 5.7	Overview of Boehringer Ingelheim's Kinase Pipeline by Status
   Table 5.8	Overview of Bristol-Myers Squibb's Kinase Pipeline by Status
   Table 5.9	Overview of Cephalon's Kinase Pipeline by Status
   Table 5.10	Overview of Deciphera Pharmaceuticals' Kinase Pipeline by Status
   Table 5.11	Overview of Eli Lilly's Kinase Pipeline by Status
   Table 5.12	Overview of Exelixis' Kinase Pipeline by Status
   Table 5.13	Overview of GlaxoSmithKline's Kinase Pipeline by Status
   Table 5.14	Overview of Hoffmann-La Roche's Kinase Pipeline by Status
   Table 5.15	Overview of Johnson & Johnson's Kinase Pipeline by Status
   Table 5.16	Overview of Kyowa Hakko Kirin's Kinase Pipeline by Status
   Table 5.17	Overview of Novartis' Kinase Pipeline by Status
   Table 5.18	Overview of Pfizer's Kinase Pipeline by Status
   Table 5.19	Overview of Sanofi-Aventis' Kinase Pipeline by Status
   Table 5.20 	Overview of Wyeth's Kinase Pipeline by Status
   Table 6.1 	Word Prevalence of Diseases
   Table 6.2	World Pharma Market By Indication, 2008-2013 ($USM)
   Table 6.3	World Pharma Market By Region, 2008-2013 ($USM)
   Table 6.4 	Kinase Analysis (2008) And Forecasts, 2009-2013 ($USM)
   Table 6.5	Kinase Inhibitors By Geography ($USM)
   Table 6.6	Manufacturer Analysis (2008) And Forecasts, 2009-2013 ($USM)
   Table 6.7	Major Kinase Patent Indications
   Table 6.8	Major Kinase Patent Assignees

Chapter 1 Kinases as drug targets

• Kinases catalyze the phosphoryl transfer reaction from ATP to a receptor substrate (protein, lipid, or a small molecule). In addition to protein kinases (the focus of this report), non-protein kinases and kinase-related proteins play important roles in cellular phosphorylation.

• Phosphorylation of protein substrates is a fundamental and reversible mechanism for regulating protein activity in eukaryotes. Eukaryotic protein kinases are extremely heterogeneous, but share high homology over their catalytic domains.

• The majority of human protein kinases catalyze the phosphorylation of serine and threonine amino acid residues (serine/threonine kinases), but 96 catalyze the phosphorylation of tyrosine residues (tyrosine kinases).

• The human protein kinase superfamily, classified according to a scheme described by Manning and his colleagues from the Salk Institute in 2002, has 9 groups, 134 families, and 196 subfamilies.

• Kinases regulate cellular signal transduction pathways. Cell surface receptors involved in signal transduction are protein tyrosine kinases. Most of the intracellular portion is a cascade of protein phosphorylations by protein kinases and dephosphorylations by protein phosphatases.

• Aberrant kinase activity and/or overactivity has been implicated in the etiology of many human diseases. Since kinases (most of the time) positively relay signaling events, their inhibition offers a powerful therapeutic strategy.

• This chapter provides a simplified overview of selected pathways in which kinases play a key role, including MAPK; PI3K/AKT; JAK/STAT; insulin receptor; NFKB pathway; immune cell signaling; VEGF and EGFR signaling.

• Protein kinases are amenable to targeting with small molecule drugs and monoclonal antibodies: historical milestones in the development of both types of drugs are reviewed. Emerging biopharmaceuticals include gene therapies, antisense oligonucleotides and RNA interference agents.

• In preparing this report, we identified 608 kinase drugs under development by 232 originating companies. 21 (3.5%) of these drugs have been launched, and 28 (7.8%) are in Phase 3 clinical trials or beyond. A total of 173 molecular targets are under investigation.

• Most drugs in development are small molecule drugs (78.8%). By far the most popular indication is cancer (74.8%), followed by arthritis (9.4%), diabetes (5.8%), and inflammation (5.8%).

Chapter 2 Small molecule kinase inhibitor discovery

• This chapter reviews traditional and emerging approaches to small molecule kinase inhibitor discovery.

• ATP is essential for kinase activity. Type 1 ATP competitive inhibitors constitute the majority of ATP competitive inhibitors discovered. They recognize the active kinase activation loop conformation, while type 2 inhibitors recognize the inactive conformation.

• Traditional kinase inhibitor discovery took place through high-throughput screening followed by empirical lead optimization. Many scaffolds that recognize the ATP-binding site have been discovered and diversified.

• New ATP site-targeted inhibitors are being developed using a combination of methods including: analog synthesis; structure-informed design; and fragment-based assembly.

• Analogs may be synthesized and isosteric replacements used to improve potency, selectivity and ADMET properties.

• Inhibitor-kinase co-crystal structures make it possible to design hybrid compounds. Computational protocols are being developed for converting type 1 inhibitor structures into type 2 inhibitors, which promise to be more specific. A "bottom up" rational inhibitor re-design strategy has also been described.

• In fragment-based inhibitor discovery moieties that bind to different portions of the active site of the target kinase can be covalently linked to create a new ATP competitive inhibitor.

• Efforts are also aimed at the development of irreversible inhibitors and allosteric inhibitors which bind outside the ATP-binding site.

• Kinase inhibitor selectivity assays profile a drug candidate's activity against a wide variety of kinases. Kinase inhibitors may be evaluated using enzymatic (activity) assays. Millipore's KinaseProfiler Service panel incorporates 283 protein and lipid kinases.

• Unlike activity assays, binding assays allow for rapid assessment of inhibitor binding to kinases in either active or nonactive conformations. Ambit Bioscienes' KINOMEscan's scanMAX panel offers over 400 kinases for profiling.

• Cellular selectivity assays use cells engineered to report on inhibition of a particular kinase. Some cell lines have been generated through the use of reporter gene assays. Kinaxo Biotechnologies' Cellular Target Profiling Service uses immobilized kinase inhibitors.

• A variety of commercial kits are available for identification od kinase substrates. For example, Cell Signaling Technology's Tyrosine Kinase Substrate Screenining Kitoffers 95 different kinase substrates. Invitrogen's Human ProtoArray, a high-density protein microarray, contains over 8,000 proteins.

Chapter 3 Targeting kinases in cancer

• Kinase inhibitors represent the most popular class of targeted anticancer therapy under development. Protein and lipid kinases are frequently hyperactivated and/or overexpressed in tumor cells resulting in increased proliferation, evasion of apoptosis, invasion, and metastasis.

• In preparing this report, we identified 455 anticancer kinase drugs directed at a total of 122 molecular targets. Most of the drugs are small molecule multi-target kinase inhibitors. The 20 leading kinase targets (ranked by the number of drugs targeting them) are profiled in this chapter.

• The top 20 kinase targets profiled include mutationally activated (oncogenic) kinases (ABL1, FLT3, KIT, PDGFRA, PDGFRB, EGFR, MET, JAK2, and PIK3CA): kinases which sustain tumor growth (FRAP1, ERBB2, AURKA, AURKB, CDC2, CDK2, PLK1, PIK3CA, and AKT1); and kinases required in tumorigenesis (KDR, FLT1 and FLT4).

• Tumors that harbor activating mutations of the targeted kinases are exceptionally susceptible to inhibition. Resistance mutations have also now been documented for various kinases and are being targeted by second-generation inhibitors.

• Kinases belonging to the tyrosine kinase (TK) group are well represented amongst top kinase targets. This group includes well-established inhibitor targets such as ABL1 (Abl family); EGFR and ERBB2 (EGFR family); FLT3, KIT, PDGFRA, and PDGFRB (PDGFR family); and FLT1, FLT4, and KDR (VEGFR family).

• One mutated form of ABL1, T315I, is resistant to all ABL1-targeting drugs on the market. Several inhibitors active against the T315I mutant have recently entered clinical trials.

• Drugs targeting EGFR family kinases include small molecule drugs and mAbs. There are indications that small molecule inhibitors are most effective against tumors with activating mutations. Irreversible EGFR family inhibitors in development may circumvent resistance to EGFR family inhibitors.

• Inhibition of VEGF and PDGR receptors represents an approach to angiogenesis inhibition, but often leads to resistance. Several multi-target anti-angiogenic kinase inhibitors have been approved, and many more are in development.

• Drugs targeting other targets profiled are mainly at early stages of development, except anti-FRAP1 agents. Inhibitors on the market and in development are analogs of Wyeth's sirolimus (formerly rapamycin, the first cytostatic agent identified).

• PIK3C is a promising target that plays a role in multiple aspects of cancer progression. Drugs targeting PIK3CA have now entered the clinic, but remain at early stages of development.

Chapter 4 Non-cancer applications of kinase drugs

• This chapter reviews non-cancer applications of kinase drugs.

• In preparing this report, we identified 153 kinase drugs in development for indications other than cancer, directed at a total of 79 molecular targets. Most of these agents are small molecule drugs.

• The leading non-cancer applications are: rheumatoid arthritis; diabetes; inflammation; immunosuppression; ophthalmology; psoriasis; pulmonary; cardiovascular; myelodysplastic disorders; GI disorders; and pain. Many of these indications are conditions associated with chronic inflammation.

• Kinases are attractive targets in inflammatory and autoimmune diseases as they modulate the signalling pathways underlying these cellular responses and play a pivotal role in the initiation, propagation and regulation of immunologic responses.

• Multiple tyrosine kinases and cellular responses are central to the pathogenesis of RA, and candidate drugs are directed at a variety of kinase targets, includding MAPK14.

• Candidate drugs for the treatment of diabetes are also directed at a variety of kinase targets. In addition to kinase inhibitors, kinase activators are under investigation.

• Leading kinase targets (ranked by the number of drugs targeting them) are: MAPK14; FRAP1; JAK3; NTRK1; and ROCK1.

• Inhibitors of MAPK14 have long been investigated in rheumatoid arthritis, but toxicity concerns have impeded progress. MAPK14-targeting drugs are also in development for cardiovascular disease and a variety of other indications.

• FRAP1 is the target of Wyeth's sirolimus (formerly rapamycin). Several drugs on the market and in development are analogs of sirolimus and are used in drug-eluting stents for the prevention of restenosis.

• JAK3-targeting agents are being developed predominantly for use in treatment of rheumatoid arthritis, other inflammatory diseases and immunosuppression.

Chapter 5 Leading kinase drug originating companies

• In preparing this report, we identified 608 kinase drugs in commercial development by 232 originators. Table 1.8 "Kinase Agents by Originator" ranks the originators by the number of kinase drugs in active development.

• Twenty top-ranking companies are profiled in this chapter in order to provide a resource for readers seeking competitive intelligence data or planning licensing and collaborative projects in the kinase area.

• The top 20 ranking companies are the following (number of pipeline kinase drugs in parentheses): Eli Lilly (18); AstraZeneca (16); Pfizer (15); Novartis (14); Bristol-Myers Squibb (13); Deciphera Pharmaceuticals (13); Array BioPharma (11); Exelixis (11); Abbott (10); Amgen (10); GlaxoSmithKline (10); Cephalon (8); Hoffmann-La Roche (8); Ambit Biosciences (7); Avila Therapeutics (7); Boehringer Ingelheim (7); Johnson & Johnson (7); Kyowa Hakko Kirin (7); Sanofi-Aventis (7); and Wyeth (7). Wyeth is soon to be acquired by Pfizer.

• For ease of reference, company profiles are arranged in alphabetical order. Each profile includes contact details and key facts about the company, sales figures for the last fiscal year (if available), followed by descriptions of the ccompany's business, kinase-related collaborations (2005 onwards) and kinase drug pipeline.