Direct Targeting of the Ras GTPase Superfamily Through Structure- Based Design

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.

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