Direct targeting of the Ras GTPase superfamily through structure-based design

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Title: Direct targeting of the Ras GTPase superfamily through structure-based design
Authors: Zhao, W
Jamshidiha, M
Lanyon-Hogg, T
Recchi, C
Cota, E
Tate, EW
Item Type: Journal Article
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.
Issue Date: 19-Jul-2016
Date of Acceptance: 20-Mar-2016
URI: http://hdl.handle.net/10044/1/39223
DOI: 10.2174/1568026616666160719165633
ISSN: 1873-4294
Publisher: Bentham Science Publishers
Start Page: 16
End Page: 29
Journal / Book Title: Current Topics in Medicinal Chemistry
Volume: 16
Issue: 1
Copyright Statement: © 2017 Bentham Science Publishers.
Sponsor/Funder: Breast Cancer Campaign
Medical Research Council (MRC)
Cancer Research UK
Funder's Grant Number: 2012NovSP035
MC_PC_13064
20781
Keywords: Science & Technology
Life Sciences & Biomedicine
Chemistry, Medicinal
Pharmacology & Pharmacy
Cancer
Fragment-based drug design
GTPase
Structure-based drug design
Rab
Ras
X-ray crystallography
PROTEIN-PROTEIN INTERACTIONS
SMALL-MOLECULE INHIBITORS
MEDIATED NUCLEOTIDE EXCHANGE
ONCOGENIC K-RAS
DRUG DISCOVERY
RHO-GTPASES
EFFECTOR INTERACTIONS
RATIONAL DESIGN
THERAPEUTIC TARGET
TUMOR PROGRESSION
Drug Delivery Systems
Drug Design
Molecular Structure
ras Proteins
0304 Medicinal And Biomolecular Chemistry
Medicinal & Biomolecular Chemistry
Publication Status: Published
Appears in Collections:Division of Surgery
Chemistry
Biological and Biophysical Chemistry
Division of Cancer
Faculty of Medicine
Faculty of Natural Sciences



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