Methods in Enzymology Volume 548 Protein Kinaase Inhibitors in Reseach and Medicine 1st edition by Kevan Shokat ISBN 978 – 0123979186 0123979188

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ISBN 10 : 0123979188

ISBN 13:  978-0123979186

Author:  Kevan M Shokat

This new volume of Methods in Enzymology continues the legacy of this premier serial with quality chapters authored by leaders in the field. This is the second of two volumes covering 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.

• Second of two volumes focusing on protein kinase inhibitors in research and medicine
• Part of the Methods in Enzymology serial with authors who are experts in their disciplines

 

Methods in Enzymology Volume 548 Protein Kinaase Inhibitors in Reseach and Medicine 1st Table of contents:

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

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