Abstract
The Ras superfamily of small monomeric GTPases includes some of the most prominent cancer targets for which no selective therapeutic agent has yet been successfully developed. The turn of the millennium saw a resurgence of efforts to target these enzymes using new and improved biophysical techniques to overcome the perceived difficulties of insurmountably high affinity for guanosine nucleotides and flat, flexible topology lacking suitable pockets for small molecule inhibitors. Further, recent investigations have begun to probe the dynamic conformational status of GTP-bound Ras, opening up new mechanisms of inhibition. While much of the literature has focused on the oncogenic Ras proteins, particularly K-Ras, these represent only a small minority of therapeutically interesting targets within the superfamily; for example, the Rab GTPases are the largest subfamily of about 70 members, and present an as yet untapped class of potential targets. The present review documents the key methodologies employed to date in structure-guided attempts to drug the Ras GTPases, and forecasts their transferability to other similarly challenging proteins in the superfamily.
Keywords: Cancer, Fragment-based drug design, GTPase, Structure-based drug design, Rab, Ras, X-ray crystallography.
Current Topics in Medicinal Chemistry
Title:Direct Targeting of the Ras GTPase Superfamily Through Structure- Based Design
Volume: 17 Issue: 1
Author(s): Wenye Zhao, Mostafa Jamshidiha, Thomas Lanyon-Hogg, Chiara Recchi, Ernesto Cota and Edward W. Tate
Affiliation:
Keywords: Cancer, Fragment-based drug design, GTPase, Structure-based drug design, Rab, Ras, X-ray crystallography.
Abstract: The Ras superfamily of small monomeric GTPases includes some of the most prominent cancer targets for which no selective therapeutic agent has yet been successfully developed. The turn of the millennium saw a resurgence of efforts to target these enzymes using new and improved biophysical techniques to overcome the perceived difficulties of insurmountably high affinity for guanosine nucleotides and flat, flexible topology lacking suitable pockets for small molecule inhibitors. Further, recent investigations have begun to probe the dynamic conformational status of GTP-bound Ras, opening up new mechanisms of inhibition. While much of the literature has focused on the oncogenic Ras proteins, particularly K-Ras, these represent only a small minority of therapeutically interesting targets within the superfamily; for example, the Rab GTPases are the largest subfamily of about 70 members, and present an as yet untapped class of potential targets. The present review documents the key methodologies employed to date in structure-guided attempts to drug the Ras GTPases, and forecasts their transferability to other similarly challenging proteins in the superfamily.
Export Options
About this article
Cite this article as:
Zhao Wenye, Jamshidiha Mostafa, Lanyon-Hogg Thomas, Recchi Chiara, Cota Ernesto and Tate W. Edward, Direct Targeting of the Ras GTPase Superfamily Through Structure- Based Design, Current Topics in Medicinal Chemistry 2017; 17 (1) . https://dx.doi.org/10.2174/1568026616666160719165633
DOI https://dx.doi.org/10.2174/1568026616666160719165633 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Dual-Targeted Molecular Probes for Cancer Imaging
Current Pharmaceutical Biotechnology Nanomedicine Strategies for Sustained, Controlled and Targeted Treatment of Alzheimer’s Disease
Mini-Reviews in Medicinal Chemistry Patent Selections
Recent Patents on Inflammation & Allergy Drug Discovery Radiolabeled Glucose Derivatives for Tumor Imaging Using SPECT and PET
Current Medicinal Chemistry The Role of Brain Cholesterol and its Oxidized Products in Alzheimer's Disease
Current Alzheimer Research Promises of Apoptosis-Inducing Peptides in Cancer Therapeutics
Current Pharmaceutical Biotechnology Ellipticines as DNA-Targeted Chemotherapeutics
Current Medicinal Chemistry Systems Biology of Apoptosis and Survival: Implications for Drug Development
Current Pharmaceutical Design Evolution of the Strategies for Screening and Identifying Human Tumor Antigens
Current Protein & Peptide Science The Use of Anthracyclines for Therapy of CNS Tumors
Anti-Cancer Agents in Medicinal Chemistry Metabolomics and the Diagnosis of Human Diseases -A Guide to the Markers and Pathophysiological Pathways Affected
Current Medicinal Chemistry Gold Nanostructures as Photothermal Therapy Agent for Cancer
Anti-Cancer Agents in Medicinal Chemistry Chemosensitization by Antisense Oligonucleotides Targeting MDM2
Current Cancer Drug Targets Regulatory Effects of N-3 PUFAs on Pancreatic β-cells and Insulin-sensitive Tissues
Current Drug Metabolism Peptides for In Vivo Target-Specific Cancer Imaging
Mini-Reviews in Medicinal Chemistry Applications of Lipid based Formulation Technologies in the Delivery of Biotechnology-based Therapeutics
Current Pharmaceutical Biotechnology Has Bevacizumab (Avastin) Given Extra Therapeutic Gain in Metastatic Colorectal Cancer and Malignant Brain Gliomas? Systematic Review Answering this Question
Recent Patents on Inflammation & Allergy Drug Discovery Translational Optical Imaging in Diagnosis and Treatment of Cancer
Current Pharmaceutical Biotechnology Curcumin: Not So Spicy After All
Mini-Reviews in Medicinal Chemistry The Role of 3D Pharmacophore Mapping Based Virtual Screening for Identification of Novel Anticancer Agents: An Overview
Current Topics in Medicinal Chemistry