Inhibitors of the Ras Superfamily G-proteins, Part A

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