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