• Jon J G Winter, Malcolm Anderson, Kevin Blades, Claire Brassington, Alexander L Breeze, Christine Chresta, Kevin Embrey, Gary Fairley, Paul Faulder, M Raymond V Finlay, Jason G Kettle, Thorsten Nowak, Ross Overman, S Joe Patel, Paula Perkins, Loredana Spadola, Jonathan Tart, Julie A Tucker, and Gail Wrigley.
• AstraZeneca , Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom.
• J. Med. Chem. 2015 Mar 12; 58 (5): 2265-74.

AbstractConstitutively active mutant KRas displays a reduced rate of GTP hydrolysis via both intrinsic and GTPase-activating protein-catalyzed mechanisms, resulting in the perpetual activation of Ras pathways. We describe a fragment screening campaign using X-ray crystallography that led to the discovery of three fragment binding sites on the Ras:SOS complex. The identification of tool compounds binding at each of these sites allowed exploration of two new approaches to Ras pathway inhibition by stabilizing or covalently modifying the Ras:SOS complex to prevent the reloading of Ras with GTP. Initially, we identified ligands that bound reversibly to the Ras:SOS complex in two distinct sites, but these compounds were not sufficiently potent inhibitors to validate our stabilization hypothesis. We conclude by demonstrating that covalent modification of Cys118 on Ras leads to a novel mechanism of inhibition of the SOS-mediated interaction between Ras and Raf and is effective at inhibiting the exchange of labeled GDP in both mutant (G12C and G12V) and wild type Ras.

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