Inhibitors of the Ras Superfamily G-proteins, Part A

Inhibitors of the Ras Superfamily G-proteins, Part A

1st Edition - August 8, 2013

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  • Editor: Fuyuhiko Tamanoi
  • Hardcover ISBN: 9780124167490
  • eBook ISBN: 9780124169678

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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.

Key Features

  • 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

Table of Contents

  • 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



    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


    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


    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


    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



    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



    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



    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


    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



    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



    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



    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


    Author Index

    Subject Index

Product details

  • No. of pages: 364
  • Language: English
  • Copyright: © Academic Press 2013
  • Published: August 8, 2013
  • Imprint: Academic Press
  • Hardcover ISBN: 9780124167490
  • eBook ISBN: 9780124169678

About the Serial Volume Editor

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, USA

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