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.
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