Kinase Therapeutic Pipelines: An Assessment of Targets and Agents in Development
Chapter 1
KINASES
1.1. The Function of Kinases
1.2. The Human Kinome
1.3. Kinase Classification
AGC Family
CAMK Family
CMGC Family
CK1 Family
STE Family
TK Family
TKL Family
Atypical Protein Kinases
1.4. Kinase Structure
1.5. Kinases as Drug Targets
Chapter 2
CURRENT COMMERCIAL SUCCESSES
2.1. Small-Molecule Kinase Inhibitors
Gleevec
Iressa and Tarceva
Nexavar
Sutent
Rapamune and Certican
2.2. Biological Agents
Chapter 3
INDICATIONS FOR THE USE OF KINASE INHIBITORS
3.1. Cancer
3.2. Angiogenic Conditions
3.3. Inflammatory Diseases
3.4. Metabolic Disorders
3.5. Central Nervous System Conditions
3.6. Cardiovascular Disease
Chapter 4
STRATEGIES FOR DEVELOPING KINASE INHIBITORS
4.1. Which Domain to Target?
4.2. Screening Approaches
4.3. Achieving Cellular Activity
4.4. Selectivity Profile
4.5. Pitfalls Encountered
4.6. Intellectual Property Issues
4.7. SWOT Analysis
Strengths
Opportunities
Weaknesses
Threats
Chapter 5
CURRENT PIPELINES
5.1. Overview of Major Company Approaches
Abbott
Amgen
AstraZeneca
Bayer Schering
Boehringer Ingelheim
Bristol-Myers Squibb
Daiichi Sankyo
Eli Lilly
GlaxoSmithKline
Johnson & Johnson
Merck & Co.
Merck Serono
Novartis
Pfizer
Roche
Sanofi-aventis
Schering-Plough
Takeda
Wyeth
5.2. Popular Targets
5.3. Drugs Targeting Protein Kinases that Have Recently Been Approved or Are
Awaiting Approval
Lapatinib
Nilotinib
Dasatinib
Sunitinib
Sorafenib
Panitumumab
5.4. Kinase Inhibitors in Phase III
Motesanib
Pazopanib
Aflibercept
Vandetanib
Cediranib
BIBW-2992
Enzastaurin and Ruboxistaurin
Deforolimus
Lestaurtinib
Alvocidib
5.5. Kinase Inhibitors in Phase II
p38 MAP Kinase Inhibitors
VX-702
SCIO-469
Pamapimod
681323 and 856553
KC-706
Other MAP Kinase Inhibitors
Atypical MAP Kinase Inhibitors
MEK Inhibitors
PD-325901
ARRY-142886
PI3K Inhibitors
Akt Inhibitors
Triciribine
Perifosine
INCB-18424
CDK and Chk Inhibitors
Chk1 Inhibitors
CDK Inhibitors
Seliciclib
Abl Inhibitors
INNO-406
AT-9283
MK-0457
AZD-0530
Bosutinib
Anti-angiogenic Kinase Inhibitors
ABT-869
AEE-788
BIBF-1120
Brivanib
RTA-402
SU-14813
SU-6668
TG-100801
XL-880
IGFR Inhibitors
INSM-18
IMC-A12
CP-751871
EGFR and ErbB2 Inhibitors
Neratinib
Flt3 Inhibitors
Lestaurtinib
Tandutinib
Inhibitors of Other Kinases
ABT-263
Masatinib
CMI X-11S
Cethrin
R-788
CP-690550
PHA-739358
BI-2536
5.6. Kinase Inhibitors in Phase I
Aurora Kinases
Raf Kinase
FGF Inhibitors
Other Kinases
5.7. Outlook
Chapter 6
SPECIALIST COMPANIES
6.1. Structure-Based Approaches
Vertex Pharmaceuticals
6.2. High-Throughput Crystallography
Astex Therapeutics
SGX Pharmaceuticals
6.3. Indication-Based Approaches
AVEO Pharmaceuticals
Cyclacel Pharmaceuticals
Kinex Pharmaceuticals
Oncalis AG
TargeGen
6.4. Domain-Focused Approaches
Ariad Pharmaceuticals
Rigel Pharmaceuticals
Kémia
Piramed Pharma
6.5. Screening-Based Approaches
Ambit Biosciences
Galápagos
Sunesis Pharmaceuticals
Upstate
6.6. Computational Approaches
4SC AG
Amphora Discovery
Aureus Pharma
Emiliem
Locus Pharmaceuticals
Chapter 7
EXPERT INTERVIEWS: A VIRTUAL ROUNDTABLE
Stephen Burley, MD, DPhil, SGX Pharmaceuticals
José Duca, PhD, Schering-Plough Research Institute
David Hayes, PhD, Millipore
Alcide Barberis, PhD, Oncalis AG
Neil Gibson, PhD, OSI Pharmaceuticals
Professor Sir Philip Cohen, FRS, FRSE, Medical Research Council Protein
Phosphorylation Unit, University of Dundee
Jeffrey Settleman, PhD, Department of Medicine, Harvard Medical School
References
Company Index with Web Addresses
FIGURES
Figure 1.1. The Human Kinome
Figure 3.1. Mitogen-Activated Protein Kinase Signaling Cascades
Figure 4.1. Selectivity Profiles of Staurosporine and 3 Marketed Protein Kinase
Inhibitors
Figure 4.2. Genetic SWOT Analysis for Kinase Inhibitors
Figure 5.1. Leading Oncology Franchises in 2006 and Proportion of Revenues
Derived from Kinase Inhibitors and Growth Factor Receptor Antibodies
Figure 5.2. Kinase Inhibitors in Development from the Major Pharmaceutical
Companies
TABLES
Table 1.1. AGC Family of Protein Kinases, Listed in Order of Phylogenetic
Similarity
Table 1.2. CAMK Family of Protein Kinases, Listed in Order of Phylogenetic
Similarity
Table 1.3. CMGC Family of Protein Kinases, Listed in Order of Phylogenetic
Similarity
Table 1.4. CK1 Family of Protein Kinases, Listed in Order of Phylogenetic
Similarity
Table 1.5. STE Family of Protein Kinases, Listed in Order of Phylogenetic
Similarity
Table 1.6. TK Family of Protein Kinases, Listed in Order of Phylogenetic
Similarity
Table 1.7. TKL Family of Protein Kinases, Listed in Order of Phylogenetic
Similarity
Table 1.8. Families of Atypical Protein Kinases
Table 2.1. 2005 and 2006 Sales of Marketed Kinase Inhibitors
Table 2.2. 2005 and 2006 Sales of Marketed Recombinant Products
Table 5.1. Recently Approved Drugs Targeting Protein Kinases
Table 5.2. Kinase Inhibitors in Phase III Studies
Table 5.3. p38 MAP Kinase Inhibitors in Clinical Development
Table 5.4. MEK Inhibitors in Clinical Development
Table 5.5. PI3K Inhibitors in Clinical Development
Table 5.6. Akt Inhibitors in Clinical Development
Table 5.7. Cell Cycle (CDK and Chk) Inhibitors in Clinical Development
Table 5.8. Abl Inhibitors in Clinical Development
Table 5.9. Anti-angiogenic Kinase Inhibitors in Clinical Development
Table 5.10. IGFR Inhibitors in Clinical Development
Table 5.11. EGFR and ErbB2 Inhibitors in Clinical Development
Table 5.12. Flt3 Inhibitors in Clinical Development
Table 5.13. Inhibitors of Other Kinases in Phase II Clinical Development
Table 5.14. Aurora Kinase Inhibitors in Phase I Studies
Table 5.15. Raf Kinase Inhibitors in Phase I Studies
Table 5.16. Pan-FGF Inhibitors in Phase I Clinical Development
Table 5.17. Other Kinase Inhibitors in Phase I Studies