Directly inhibiting oncogenic RAS proteins has proven to be an arduous task, as after more
than thirty years of intensive investigation, no clinically relevant therapies exist. Recently, two classes
of selective small molecule inhibitors that target a cysteine-containing RAS mutant have been
developed, representing the first directed approaches to specifically inhibit an oncogenic KRAS
mutant. In this mini-review, we first assess the development and targeting strategies associated with
novel cysteine-directed RAS inhibitors. Next, we describe the variable oncogenic potency of the
KRAS G12C mutant when compared to other KRAS G12 mutants. Lastly, we evaluate how the redox properties of KRAS
G12C may play a role in differential signaling and tumorigenic potency of the oncogene, the efficacy of small molecules
targeting this specific RAS mutant and further development of directed oncogenic RAS inhibitors.
Keywords: KRAS G12C, RAS inhibition, cysteine-directed inhibitors, RAS oxidation, tethering.
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