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Protein Kinase Inhibitors in Research and Medicine
1st Edition, Volume 548 - July 1, 2013
Editor: Kevan M Shokat
Language: English
Hardback ISBN:9780123979186
9 7 8 - 0 - 1 2 - 3 9 7 9 1 8 - 6
eBook ISBN:9780123984623
9 7 8 - 0 - 1 2 - 3 9 8 4 6 2 - 3
This new volume of Methods in Enzymology continues the legacy of this premier serial with quality chapters authored by leaders in the field. This volume covers protein kinase…Read more
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This new volume of Methods in Enzymology continues the legacy of this premier serial with quality chapters authored by leaders in the field. This volume covers protein kinase inhibitors in research and medicine, and includes chapters on such topics as fragment-based screening, broad kinome profiling of kinase inhibitors, and designing drug-resistant kinase alleles.
Continues the legacy of this premier serial with quality chapters authored by leaders in the field
Covers research methods in biomineralization science
Contains sections focusing on protein kinase inhibitors in research and medicine
Biochemists, biophysicists, molecular biologists, analytical chemists, and physiologists
Preface
Chapter One: Catalytic Mechanisms and Regulation of Protein Kinases
Abstract
1 Introduction
2 Kinetic Mechanism
3 Chemical Mechanism of Kinase Phosphoryl Transfer
4 Applications of Mechanistic Studies in Understanding Kinase Function and Regulation
5 Summary and Outlook
Chapter Two: A Structural Atlas of Kinases Inhibited by Clinically Approved Drugs
Abstract
1 Introduction
2 Kinase Structure and Catalytic Mechanism
3 Staurosporine: A Promiscuous ATP-Competitive Inhibitor
4 BCR-Abl Inhibitors
5 Tofacitinib (Xeljanz™) Binds to a “DFG-in” Conformation of Janus Kinase
6 Inhibition of Receptor Tyrosine Kinases
7 Vemurafenib (Zelboraf™) Binds to A “DFG-in” Conformation in the Ser/Thr Kinase RAF
8 Inhibitors That Occupy Pockets Other Than the ATP-Binding Site
9 Summary
Acknowledgments
Chapter Three: Fragment-Based Approaches to the Discovery of Kinase Inhibitors
Abstract
1 Introduction
2 Fragment-Based Drug Discovery
3 Identifying Fragment Hits
4 From Fragments to Leads
5 Alternative Inhibition Strategies
6 Summary
Acknowledgments
Chapter Four: Targeting Protein Kinases with Selective and Semipromiscuous Covalent Inhibitors
Abstract
1 Introduction
2 Design of Irreversible Cysteine-Targeted Kinase Inhibitors
3 Targeting Noncatalytic Cysteines with Reversible Covalent Inhibitors
4 Semipromiscuous Covalent Inhibitors as Chemoproteomic Probes
5 Conclusions and Future Directions
Chapter Five: The Resistance Tetrad: Amino Acid Hotspots for Kinome-Wide Exploitation of Drug-Resistant Protein Kinase Alleles
Abstract
1 Introduction
2 Protein Kinases and Kinase Inhibitors
3 Protein Kinase Inhibitors
4 Screening Approaches to Decipher Protein Kinase-Inhibitor Specificity
5 Random and Directed Mutagenesis Approaches Reveal Common Resistance Mechanisms
6 A General Procedure for Directed (Nonrandom) Mutagenesis of dsDNA Plasmids
7 The Resistance Tetrad Position 0: The Gatekeeper Residue
8 SB203580: A Paradigm for Gatekeeper-Mediated Drug Resistance from Test Tube to Mouse
9 Expanding the Resistance Tetrad: + 2 (Hydrophobic) and + 6/+ 7 Specificity Surfaces in Kinases
10 The Resistance Tetrad is a Selectivity Filter Applicable for Kinome-Wide Drug-Resistance Studies
11 Engineering and Analysis of Logically Designed Drug-Resistance Mutations
12 Analysis of Inhibitor Resistance Toward WT and DR Mutants In Vitro
13 Oncogenic Gatekeeper Mutations: Unanticipated Mechanisms of Gatekeeper Resistance Merit Biochemical Scrutiny of DR Mutants
14 Evaluation of Catalytic Behavior and KM[ATP] Value for WT and DR Kinase Mutants In Vitro
15 Intact Cell Systems for Analyzing Drug Resistance and Target Validation
16 Generation of Stable, Isogenic Cell Lines Expressing Tetracycline-Inducible Kinases
17 Analysis of Kinase Drug Resistance Toward a Cytotoxic Inhibitor: Cell Growth Assay Based on Colony Formation (Fig. 5.2F)
18 Conclusions
Chapter Six: FLiK: A Direct-Binding Assay for the Identification and Kinetic Characterization of Stabilizers of Inactive Kinase Conformations
Abstract
1 Introduction
2 Design and Preparation of Kinases for FLiK
3 Labeling of p38α MAP Kinase with Acrylodan
4 Assay Characterization and Validation
5 HTS with FLiK
6 Summary
Acknowledgments
Chapter Seven: Discovery of Allosteric Bcr–Abl Inhibitors from Phenotypic Screen to Clinical Candidate
Abstract
1 Development of ATP-Site-Directed Inhibitors of BCR–ABL for the Treatment of CML
2 Discovery and Characterization of Non-ATP-Site-Directed BCR–ABL Inhibitors
3 Characterization of the Binding of the Non-ATP-Site-Directed Bcr–ABL Inhibitor GNF-2
4 Therapeutic Potential of First-Generation myr-Pocket Binders
5 Combinations of Second-Generation ATP-Site Inhibitors with Second-Generation myr-Pocket Ligands
Acknowledgments
Chapter Eight: The Logic and Design of Analog-Sensitive Kinases and Their Small Molecule Inhibitors
Abstract
1 Introduction
2 Constructing AS Kinases
3 AS Kinase Inhibitors
4 AS Kinases in Cells
5 AS Kinases in Living Multicellular Organisms
6 Summary
Author Index
Subject Index
No. of pages: 252
Language: English
Edition: 1
Volume: 548
Published: July 1, 2013
Imprint: Academic Press
Hardback ISBN: 9780123979186
eBook ISBN: 9780123984623
KS
Kevan M Shokat
Professor Kevan is currently an Investigator of the Howard Hughes Medical Institute, Chair of the Department of Cellular and Molecular Pharmacology at UCSF and a Professor of Chemistry at UC Berkeley. He was inducted into the National Academy of Sciences (2010), the Institute of Medicine (2011), and the American Academy of Arts and Sciences (2011). His lab is most well-known for drugging the "undruggable" oncogene K-Ras (G12C) in 2013. In May of 2021 the drug sotorasib which binds to the same pocket on K-Ras (G12C) was approved for the treatment of lung cancer patients with this mutation. The field of K-Ras drug discovery is expanding quickly to hunt for drugs to target the other K-Ras mutants such as those which drive colon and pancreatic cancers which collectively represent almost 20% of all cancer patients world-wide. Kevan has been a co-founder of a number companies from their inception to public offering or acquisition and he is a co-founder of several currently private companies.
Affiliations and expertise
Department of Cellular and Molecular Pharmacology at UCSF; Professor of Chemistry at UC Berkeley; Howard Hughes Medical Institute investigator, USA
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