David J. Matthews, Mary E. Gerritsen

Targeting Protein Kinases for Cancer Therapy

• Gebundenes Buch

Produktbeschreibung

This book provides an overview of different protein kinases - structure, function, regulation, and their role in cancer. It combines kinase biology with chemistry and pharmacology applications for discovery and development of cancer drugs. The text also describes existing and emerging kinase inhibitors, focusing mostly on small molecules but also alternative approaches like therapeutic antibodies. Provides an important resource that helps pharmaceutical researchers understand and work in this dynamic area of cancer drug research.

Produktdetails

• Verlag: Wiley & Sons
• 1. Auflage
• Seitenzahl: 720
• Erscheinungstermin: 1. Februar 2010
• Englisch
• Abmessung: 243mm x 164mm x 45mm
• Gewicht: 1105g
• ISBN-13: 9780470229651
• ISBN-10: 0470229659
• Artikelnr.: 27871072

Autorenporträt

DAVID J. MATTHEWS is Executive Director of Oncology Discovery at Exelixis, where he is responsible for cancer drug discovery. For more than fifteen years, Dr. Matthews has been involved in drug discovery projects in industry, with particular focus on small molecule inhibitors. He has twenty scientific publications and multiple patents to his credit. MARY E. GERRITSEN is Vice President of Molecular and Cellular Pharmacology at Exelixis, where she is in charge of cell-based screening in preclinical research and of biomarker studies for clinical development compounds in Phase I and II studies. Her prior industry experience includes positions at Genentech, Bayer and Millennium Pharmaceuticals. She has authored more than one hundred peer-reviewed articles and twenty-six book chapters and is an inventor on forty-two issued patents.

Inhaltsangabe

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.
1.3.1 Tyrosine Kinase Group. 1.3.2 TKL (Tyrosine Kinase-Like) Group. 1.3.3
STE Group. 1.3.4 CSNK1 Group. 1.3.5 AGC group. 1.3.6 CAMK Group. 1.3.7 CMGC
Group. 1.3.8 RGC Group. 1.3.9 Others. 1.3.10 Atypical Protein Kinases.
1.3.11 Non-Protein Kinases. 1.4 Strategic Considerations for Selecting
Kinases as Drug Targets. 1.5 Comparison of Kinase Inhibitor Therapeutic
Strategies. 1.5.1 Small molecule vs. antibody-directed therapies. 1.5.2
Alternative strategies for kinase inhibition. 2 Protein Kinase Structure,
Function And Regulation. 2.1 Ligand Binding to Receptor Tyrosine Kinases.
2.1.1 EGF:EGF Receptor Interactions. 2.1.2 Insulin:Insulin Receptor and
IGF1:IGF1R. 2.1.3 FGF:FGF Receptor (heparin/heparan sulphate) Interactions.
2.1.4 VEGF:VEGF Receptor Interactions. 2.1.5 Angiopoietin2:TIE2 Receptor
Interactions. 2.1.6 Ephrin:EPH Receptor Interactions. 2.1.7 The Role of
Transmembrane Domains. 2.2 Protein Kinase Domain Structure and Function.
2.3 Catalytic Activity of Protein Kinases. 2.3.1 Steady State Kinetics.
2.3.2 Chemistry of Protein Kinase Catalysis. 2.4 Protein Kinase Regulation.
2.4.1 Regulation via activation segment phosphorylation. 2.4.2 Regulation
by N-terminal Sequences and Domains. 2.4.3 C-terminal Regulatory Regions.
2.4.4 Regulation by other domains and partner proteins. 3 Receptor Tyrosine
Kinases. 3.1 EGF/ERBB Receptors. 3.1.1 ERBB Receptors and Cancer. 3.2
Insulin/IGF Receptors. 3.2.1 Insulin/IGF Receptors and Cancer. 3.3
Anaplastic Lymphoma Kinase (ALK). 3.3.1 ALK and Cancer. 3.4 VEGF receptors
(VEGFR1, VEGFR2, VEGFR3). 3.5 PDGF Receptors. 3.5.1 PDGF Receptors and
Cancer. 3.6 FGF Receptors. 3.6.1 FGF Receptors and Cancer. 3.7 KIT. 3.7.1
KIT and Cancer. 3.8 FLT3. 3.8.1 FLT3 and Cancer. 3.9 RET. 3.9.1 RET and
Thyroid Carcinoma. 3.10 MET (HGF receptor) and RON (MSP receptor). 3.10.1
MET. 3.10.2 RON. 4 Non-Receptor Tyrosine Kinases. 4.1 ABL. 4.2 ARG. 4.3 SRC
and SRC family kinases. 4.3.1 SRC. 4.3.2 Cellular Roles of SRC. 4.3.3 SRC
and Cancer. 4.4 FAK. 4.4.1 FAK and Cancer. 4.5 JAK2. 4.5.1 Activation and
known mutations and fusions of the JAK family of tyrosine kinases. 4.5.2
Further roles of JAK2 in tumor growth. 5 Intracellular Signal Transduction
Cascades. 5.1 The PI3K/PTEN Pathway. 5.1.1 PI-3 kinase. 5.1.2 PDK1. 5.1.3
AKT. 5.1.4 Other AGC kinases. 5.1.5 PI3K Pathway Activation in Cancer. 5.2
mTOR Signaling. 5.2.1 mTOR. 5.2.2 p70S6 Kinase. 5.2.3 mTOR Pathway
Activation in Cancer. 5.3 MAPK signaling pathways. 5.3.1 ERK/MAPK
signaling. 5.3.2 RAF family kinases. 5.3.2 MEK and ERK kinases. 5.3.3
ERK/MAPK Pathway Activation in Cancer. 5.4 PIM kinases. 5.5 Protein Kinase
C. 5.5.1 PKC Activation. 5.5.2 Classical PKCs. 5.5.3 Novel PKCs. 5.5.4
Atypical PKCs. 6 Cell Cycle Control. 6.1 Cyclin-Dependent Kinases (CDKs)
and Cell Cycle Progression. 6.1.1 Introduction. 6.1.2 CDK4 and CDK6. 6.1.3
CDK2. 6.1.4 CDK3. 6.1.5 CDK1. 6.1.6 CDK10. 6.1.7 CCRK/ CDCH/ p42. 6.2 CDKs
and mRNA Production. 6.2.1 Introduction. 6.2.2 CDK7. 6.2.3 CDK8. 6.2.4
CDK9. 6.2.5 CDK11. 6.2.6 CDK12 (CDC2-related kinase CRKRS). 6.2.7 CDK13
(CDC2L5). 6.3 Other CDK-related kinases. 6.3.1 CDK5. 6.3.2 GAK. 6.4 Mitotic
Kinases. 6.4.1 Polo-like kinases. 6.4.2 Aurora Kinases. 6.5 Cell Cycle
Checkpoint Kinases. 6.5.1 ATM, ATR and DNAPK. 6.5.2 CHK1, CHK2 and
MAPKAPK2. 7 Structural Biochemistry of Kinase Inhibitors. 7.1 Strategies
for Inhibitor Design. 7.1.1 Targeting the Active vs. Inactive Form. 7.1.2
ATP-competitive vs. Noncompetitive Inhibitors. 7.1.3 Specific vs.
Multi-targeted Inhibitors. 7.2 Architecture of the ATP-binding site:
DFG-in. 7.3 Case Study: Inhibitors of CHK1 Kinase. 7.4 Case Study:
Inhibitors of CDK2 Kinase. 7.5 Case Study: Inhibitors of SRC Family
Kinases. 7.6 Case Study: EGF Receptor Inhibitors. 7.7 Targeting the
inactive conformation. 7.7.1 Binding mode of imatinib. 7.7.2 Binding of
BAY-43-9006 (sorafenib) to the inactive B-RAF kinase. 7.8 Noncompetitive
inhibition. 7.9 Kinase inhibitor specificity. 8 Tyrosine Kinase Inhibitors.
8.1 BCR-ABL Inhibitors. 8.2 SRC inhibitors. 8.3 JAK2 inhibitors. 8.4
EGFR/ERBB Inhibitors. 8.4.1 Determinants of response and resistance to ERBB
inhibitors. 8.5 IGFR inhibitors. 8.6 FLT3 inhibitors. 8.7 KIT inhibitors.
8.8 MET/RON Inhibitors. 8.9 RET Inhibitors. 8.10 Other Inhibitors. 8.10.1
Focal Adhesion Kinase. 8.10.2 TGF? Receptor. 9 Angiokinase Inhibitors. 9.1
Introduction. 9.2 Angiokinase inhibitors. 10 Intracellular Signaling Kinase
Inhibitors. 10.1 mTOR Inhibitors. 10.1.1 Clinical Pharmacodynamics and
Tolerability of mTOR Inhibitors. 10.2 PI-3 Kinase 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. 10.7.1
PLK (Polo-like Kinase) Inhibitors. 10.7.2 Aurora Kinase Inhibitors. 10.8
Protein Kinase C Inhibitors. 11 Current Challenges and Future Directions.
11.1 Kinase Inhibitor Drug Resistance. 11.1.1 Efflux Pumps and Drug
Transporters. 11.1.2 Other DMPK factors. 11.1.3 Target Mutation. 11.1.4
Target Overexpression and Activation. 11.1.5 Downstream Pathway Activation.
11.1.6 Redundant Receptors/Pathways. 11.2 Combination Therapy with Kinase
Inhibitors. 11.2.1 Angiogenesis inhibitors and chemotherapy. 11.2.2
Survival pathway inhibitors and chemotherapy/targeted therapy. 11.2.3 DNA
damage checkpoint inhibitors and chemotherapy. 11.2.4 RTK switching:
Targeting receptor redundancy. 11.3 Systems Biology and Translational
Medicine. 11.3.1 Classification of tumors and prediction of response:
Expression profiling. 11.3.2 Phosphoprotein analysis, Kinomics and
Systems-based Approaches. 11.3.3 Translational Medicine. 11.4 Conclusions.