Inhibitors of the Ras Superfamily G-proteins, Part A

1st Edition, Volume 33 - August 8, 2013
Editor: Fuyuhiko Tamanoi
Language: English
Hardback ISBN:
9 7 8 - 0 - 1 2 - 4 1 6 7 4 9 - 0
eBook ISBN:
9 7 8 - 0 - 1 2 - 4 1 6 9 6 7 - 8

This special volume of The Enzymes is targeted toward researchers in biochemistry, molecular and cell biology, pharmacology, and cancer. This thematic volume discusses inhibitor… Read more

Inhibitors of the Ras Superfamily G-proteins, Part A

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This special volume of The Enzymes is targeted toward researchers in biochemistry, molecular and cell biology, pharmacology, and cancer. This thematic volume discusses inhibitors of the Ras superfamily G-proteins.

Chapter One. The Ras Superfamily G-Proteins

1 The Ras Superfamily G-Proteins

2 Overview of Structure, Activity, and Regulatory Proteins

3 Upstream and Downstream Signaling Pathways

4 Significance in Human Cancer

5 Strategies to Inhibit the Ras Superfamily G-Proteins

Acknowledgments

References

Chapter Two. NMR Study to Identify a Ligand-Binding Pocket in Ras

1 KRAS as a Drug Target

2 Nuclear Magnetic Resonance Fragment Screen

3 Protein Ligand Co-structures

4 Inhibition of SOS1-Mediated Nucleotide Exchange for RAS

5 Ligand-Binding Sites on Ras

6 Summary and Conclusions

References

Chapter Three. The Allosteric Switch and Conformational States in Ras GTPase Affected by Small Molecules

1 Introduction

2 Ras Architecture: The G Domain and Its Function

3 The Allosteric Switch in Ras-GTP and Its Role in Intrinsic Hydrolysis

4 The Allosteric Switch Linked to the Ras/Raf/MEK/ERK Pathway

5 Most Ras Structures in the Protein Data Bank are in the R State

6 Modulation of the Allosteric States in Ras-GTP by Small Molecules

7 Mapping the Binding Site Hot Spots in Ras: Targeting the Protein/Membrane Interface

8 Conclusions

References

Chapter Four. State 1(T) Inhibitors of Activated Ras

1 Introduction

2 Allosteric Regulation of the Ras–Effector Interaction

3 Identification of State 1(T) in Activated Ras by NMR Spectroscopy

4 Identification of 1(T) Inhibitors by NMR Spectroscopy

5 Metal-Cyclen Derivatives as 1(T) Inhibitors

6 Metal-BPA Derivatives as 1(T) Inhibitors

7 Outlook: Possible Applications to Other Small GTPases

References

Chapter Five. Sugar-Based Inhibitors of Ras Activation: Biological Activity and Identification of Ras–Inhibitor Binding Interface

1 Introduction

2 Initial Compounds and the Characterization of Ras–GDP Complex

3 New Ras Ligands from Natural Sugars

4 Ras Inhibitors with Improved Water Solubility

5 Conclusions

Acknowledgments

References

Chapter Six. Development of EHop-016: A Small Molecule Inhibitor of Rac

1 Introduction

2 Development of Rac Inhibitors to Impede Metastatic Cancer Progression

3 Future Directions

Acknowledgments

References

Chapter Seven. Aptamer-Derived Peptide Inhibitors of Rho Guanine Nucleotide Exchange Factors

1 Introduction

2 The Peptide Aptamer Technology: A Brief Overview

3 The Peptide Aptamer Technology Applied to the Identification of RhoGEF Inhibitors: Example of TRIPα Aptamer Targeting Trio

4 Peptide Aptamer Optimization as a Strategy to Identify Inhibitors of the Oncogenic RhoGEF Tgat

5 Conclusion—Perspectives

Acknowledgments

References

Chapter Eight. Targeting the Dbl and Dock-Family RhoGEFs: A Yeast-Based Assay to Identify Cell-Active Inhibitors of Rho-Controlled Pathways

1 Introduction

2 The YEA: Rationale and Principle

3 Applications

4 Concluding Remarks

5 Materials and Methods

References

Chapter Nine. Inhibitors of the ROCK Serine/Threonine Kinases: Key Effectors of the RhoA Small GTPase

1 Introduction

2 Fasudil and Y-27632

3 Proper Use of ROCK Inhibitors as Tools

4 Next-Generation ROCK Inhibitors

5 Future Directions for the Development of ROCK Inhibitors

6 Conclusions

Acknowledgments

References

Chapter Ten. A Two-Hybrid Approach to Identify Inhibitors of the RAS–RAF Interaction

1 Introduction

2 Outline of Discovery Process for MCP Compounds

3 Creation of a Y2H Strain with Improved Permeability

4 Selection of Novel RAS–RAF Protein Interaction Inhibitors in HTS in Hyperpermeable Yeast SKY54

5 Evaluation of Y2H-selected Compounds in SRE- and AP-1-Luciferase Secondary Screens in Mammalian Cell Lines

6 MCP Compounds Inhibit RAS-Induced Phosphorylation of the MAPK Pathway Kinases

7 MCP Compounds Block the Interaction between RAS and the RAF-RBD

8 Computational Docking of MCP110 to RAF

9 Probing the Anticancer Activity of MCP Compounds in Multiple Tumor Types

10 MCP Compounds Synergize with MAPK Pathway Inhibitors and Microtubule-Targeting Chemotherapeutics

11 Activity of MCP Compounds in Animal Models

12 Conclusion

Acknowledgments

References

Chapter Eleven. Inhibitors of K-Ras Plasma Membrane Localization

1 Introduction

2 Discovery Process for Inhibitors of Ras PM Localization

3 Staurosporines Inhibit Ras PM Localization by Blocking Phosphatidylserine Trafficking

4 Fendiline Inhibits K-Ras PM Targeting by an Off-Target Mechanism that is Unrelated to Calcium Channel Blockade

5 Metformin: A New Use as an Anticancer Therapeutic Targeting K-Ras

6 Conclusion and Future Directions

Acknowledgment

References

Chapter Twelve. Ras Chaperones: New Targets for Cancer and Immunotherapy

1 Introduction

2 Ras Chaperones are Targets for Ras Inhibition

3 FTS Analogs for Cancer Therapy

4 FTS in Combination with Other Agents for Cancer Therapy

5 Inhibition of Ras-Related Proteins by FTS

6 Ras in Orphan Diseases

7 FTS in the Immune System

8 FTS and Autoimmunity

9 FTS in Other Disease Models

10 Conclusions

References

Author Index

Subject Index

Life Sciences

Physical Sciences & Engineering

Social Sciences & Humanities

Health

Inhibitors of the Ras Superfamily G-proteins, Part A

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Fuyuhiko Tamanoi