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Small Molecule Binding Sites on the Ras:SOS Complex Can Be Exploited for Inhibition of Ras Activation

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AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom
*E-mail: [email protected]. Phone: +44 (0)1625 582 828.
Cite this: J. Med. Chem. 2015, 58, 5, 2265–2274
Publication Date (Web):February 19, 2015
Copyright © 2015 American Chemical Society

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    Constitutively 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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    Nuclear magnetic resonance KD determinations, mass spectrometry analysis of covalent adduction to proteins, crystallographic system Ras:Raf HTRF assays, MANT-dGDP nucleotide exchange assays, and compound synthesis. This material is available free of charge via the Internet at

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    PDB accession codes are the following: 4URU, 4URV, 4URW, 4URX, 4URY, 4URZ, 4US0, 4US1, 4US2.

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