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Protein Kinase Inhibitors in Research and Medicine - 1st Edition - ISBN: 9780123979186, 9780123984623

Protein Kinase Inhibitors in Research and Medicine, Volume 548

1st Edition

Serial Volume Editor: Kevan Shokat
Hardcover ISBN: 9780123979186
eBook ISBN: 9780123984623
Imprint: Academic Press
Published Date: 12th November 2014
Page Count: 252
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Table of Contents

  • 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


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.

Key Features

  • 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


No. of pages:
© Academic Press 2014
12th November 2014
Academic Press
Hardcover ISBN:
eBook ISBN:

Ratings and Reviews

About the Serial Volume Editor

Kevan Shokat

Affiliations and Expertise

Department Cellular and Molecular Pharmacology, University of California San Francisco, CA, USA