An expert guide to targeting protein kinases in cancer therapy Research has shown that protein kinases can instigate the formation and spread of cancer when they transmit faulty signals inside cells. Because of this fact, pharmaceutical scientists have targeted kinases for intensive study, and have been working to develop medicinal roadblocks to sever their malignant means of communication.
Complete with full-color presentations, Targeting Protein Kinases for Cancer Therapy defines the structural features of protein kinases and examines their cellular functions. Combining kinase biology with chemistry and pharmacology applications, this book enlists emerging data to drive the discovery of new cancer-fighting drugs. Valuable information includes:
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Comprehensive overviews of the major kinase families involved in oncology, integrating protein structure and function, and providing important tools to assist pharmaceutical researchers to understand and work in this dynamic area of cancer drug research
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Focus on small molecule inhibitors as well as other therapeutic modalities
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Discussion of kinase inhibitors that have entered clinical trials for the treatment of cancer, with an emphasis on molecules that have progressed to late stage clinical trials and, in a few cases, to market
Providing a platform for further study, this important work reviews both the successes and challenges of kinase inhibitor therapy, and provides insight into future directions in the war against cancer.
An expert guide to targeting protein kinases in cancer therapyResearch has shown that protein kinases can instigate the formation and spread of cancer when they transmit faulty signals inside cells. Because of this fact, pharmaceutical scientists have targeted kinases for intensive study, and have been working to develop medicinal roadblocks to sever their malignant means of communication.
Complete with full-color presentations, Targeting Protein Kinases for Cancer Therapy defines the structural features of protein kinases and examines their cellular functions. Combining kinase biology with chemistry and pharmacology applications, this book enlists emerging data to drive the discovery of new cancer-fighting drugs. Valuable information includes:
Comprehensive overviews of the major kinase families involved in oncology, integrating protein structure and function, and providing important tools to assist pharmaceutical researchers to understand and work in this dynamic area of cancer drug research
Focus on small molecule inhibitors as well as other therapeutic modalities
Discussion of kinase inhibitors that have entered clinical trials for the treatment of cancer, with an emphasis on molecules that have progressed to late stage clinical trials and, in a few cases, to market
Providing a platform for further study, this important work reviews both the successes and challenges of kinase inhibitor therapy, and provides insight into future directions in the war against cancer.
Arvustused
"The comprehensive coverage makes the book highly recommendable for beginners and expert researchers in oncology and should be present on their shelves." ( ChemMedChem , November 2010)
Preface. Acknowledgments. 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 Versus
Antibody-Directed Therapies. 1.5.2 Alternative Strategies for Kinase
Inhibition. References. 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. References. 3 RECPETOR 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. 3.3.1 ALK and Cancer. 3.4 VEGF Receptors (VEGFR1, VEGFR2, VEGFR3).
3.5 PDGF Receptors. 3.5.1 PDGFRs and Cancer. 3.6 FGF Receptors. 3.6.1 FGFRs
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 and RON. 3.10.1 MET.
3.10.2 RON. References. 4 NONRECEPTOR 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. References. 5 INTRACELLULAR SIGNAL
TRANSDUCTION CASCADES. 5.1 The PI3K/PTEN Pathway. 5.1.1 PI3K. 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. 5.3.3 MEK and ERK Kinases. 5.3.4 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.
References. 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
PLKs. 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. References. 7 STRUCTURAL
BIOCHEMSITRY OF KINASE INHIBITORS. 7.1 Strategies for Inhibitor Design.
7.1.1 Targeting the Active Versus Inactive Form. 7.1.2 ATP-Competitive Versus
Noncompetitive Inhibitors. 7.1.3 Specific Versus Multitargeted Inhibitors.
7.2 Architecture of the ATP Binding Site: DFG-in. 7.3 Case Study: Inhibitors
of CHK1. 7.4 Case Study: Inhibitors of CDK2. 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 BRAF Kinase. 7.8 Noncompetitive
Inhibition. 7.9 Kinase Inhibitor Specificity. References. 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 IGF1R 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 FAK. 8.10.2 TGFss Receptor. References. 9 ANGIOKINASE
INHIBITORS. 9.1 Introduction. 9.2 Angiokinase Inhibitors. References. 10
INTRACELLULAR SIGNALING KINASE INHIBITORS. 10.1 mTOR Inhibitors. 10.1.1
Clinical Pharmacodynamics and Tolerability of mTOR Inhibitors. 10.2 PI3K
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 Inhibitors. 10.7.2 Aurora Kinase Inhibitors. 10.8
Protein Kinase C Inhibitors. References. 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. References. List of Abbreviations.
Index.
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.
