Inhibitors of the Ras Superfamily G-proteins, Part A
- 1st Edition, Volume 33 - August 8, 2013
- Imprint: Academic Press
- 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
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Request a sales quoteThis 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.
- Contributions from leading authorities
- Informs and updates on all the latest developments in the field
Researchers in biochemistry, molecular and cell biology, pharmacology, and cancer
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
- Edition: 1
- Volume: 33
- Published: August 8, 2013
- No. of pages (Hardback): 364
- Imprint: Academic Press
- Language: English
- Hardback ISBN: 9780124167490
- eBook ISBN: 9780124169678
FT
Fuyuhiko Tamanoi
Fuyu Tamanoi is a biochemist who has served on the UCLA School of Medicine and UCLA College faculty since he joined the Department of Microbiology, Immunology & Molecular Genetics in 1993. He became a full professor in 1997.
Affiliations and expertise
Biochemist, Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, USARead Inhibitors of the Ras Superfamily G-proteins, Part A on ScienceDirect