1. Selective Targeting of the KRAS G12C Mutant: Kicking KRAS When It’s Down 
G. Aaron Hobbs, Alfred Wittinghofer, Channing J. Der 
Cancer Cell 
Volume 29, Issue 3, Pages (March 2016)
DOI: /j.ccell
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2. Figure 1 Mechanism of Action of ARS853
(A) Covalent modification of KRASG12C locks the GTPase in the GDP-bound state. Assuming a similar structure for the GTP-bound form, GTP is occluded from the nucleotide binding site due to steric occlusion of the γ-phosphate by the carbonyl of ARS853; the carbonyl of ARS853 would be only 1.1 Å from the terminal phosphate. ARS853 binding pushes switch II into an extended conformation (cyan) while maintaining switch 1 in a GDP-like conformation, likely due to the inability to bind GTP, resulting in permanently inactivated KRASG12C. (B) Single amino acid substitutions at G12, G13, or Q61 comprise 99% of the KRAS missense mutations found in human cancers. Fifteen different amino acid substitutions are found at G12, with G12C accounting for 14% of G12 mutations. Data compiled from a total of 39,160 KRAS mutations (COSMIC v76). (C) Initial biochemical and structural studies focused on HRAS G12V, where the biochemical defects found were impaired intrinsic GTPase activity and almost complete loss of GAP-stimulated GTP hydrolysis. These findings led to the classically held notion that all mutant RAS proteins are persistently GTP bound and GEF independent. However, it is now clear that different mutations can have different biochemical consequences, including partial loss of intrinsic and GAP-stimulated GTP hydrolysis and enhanced intrinsic GDP-GTP exchange activity, and that, at steady state, each mutant might be differentially loaded. These two studies evaluated the mechanism by which ARS853 selectively blocks KRASG12C activity and signaling. ARS853 selectively recognizes the GDP-bound form of KRASG12C and perturbs KRAS function by disrupting intrinsic and GEF-stimulated GDP-GTP exchange, preventing formation of active GTP-bound KRASG12C. ARS853-induced protein conformation changes also likely disrupt effector interaction. Because RASGEF activity favors formation of KRAS-GTP, thereby decreasing the pool of KRAS susceptible to ARS853, concurrent inhibition of receptor-mediated GEF activation can potentiate ARS853 activity.
Cancer Cell  , DOI: ( /j.ccell )
Copyright © 2016 Elsevier Inc. Terms and Conditions