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Targeting oncogenic K-Ras G12C and G13C via covalent drug design


Ras proteins are part of a large superfamily of small monomeric GTPases that act as molecular switches to regulate cell signaling. Dysfunctional Ras signaling is implicated in 30% of human cancers. Of the 3 protein isoforms, H-, K-, and N-Ras, K-Ras is the most commonly mutated, particularly at residues 12 and 13. K-Ras(G12C) and K-Ras(G13C) are acquired mutations in lung and colorectal cancer, which are among the most common and deadly malignancies worldwide. Furthermore, G12C and G13C are potentially druggable mutations that are close to the switch II pocket of K-Ras. Biochemical studies reveal that K-Ras(G13C) is a fast exchanging mutant, with a potentially destabilized nucleotide binding pocket, indicating that G13C is structurally different from G12C. Despite these differences, K-Ras(G12C) and K-Ras(G13C) are both amenable to covalent drug design via computational and empirical screening methods.

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