This study reports the development of small molecules that irreversibly bind to the oncogenic K-Ras(G12C) mutant, a common activating mutation in human cancer. These compounds, which bind to a new allosteric pocket (switch-II pocket, S-IIP) formed by the mutant cysteine, disrupt both switch-I and switch-II regions, subverting the native nucleotide preference and impairing binding to Raf. Crystallographic studies reveal that the compounds do not bind in the nucleotide pocket but extend into the S-IIP, a region not visible in previous Ras structures. The binding of these inhibitors to K-Ras(G12C) shifts the nucleotide preference from GTP to GDP, leading to accumulation of the inactive state. Additionally, the compounds diminish interactions with effectors and regulatory proteins, further impairing Ras function. In cellular models, the compounds show allele-specific impairment of K-Ras(G12C) function, suggesting a potential therapeutic window for targeted inhibition of K-Ras(G12C) in cancer.This study reports the development of small molecules that irreversibly bind to the oncogenic K-Ras(G12C) mutant, a common activating mutation in human cancer. These compounds, which bind to a new allosteric pocket (switch-II pocket, S-IIP) formed by the mutant cysteine, disrupt both switch-I and switch-II regions, subverting the native nucleotide preference and impairing binding to Raf. Crystallographic studies reveal that the compounds do not bind in the nucleotide pocket but extend into the S-IIP, a region not visible in previous Ras structures. The binding of these inhibitors to K-Ras(G12C) shifts the nucleotide preference from GTP to GDP, leading to accumulation of the inactive state. Additionally, the compounds diminish interactions with effectors and regulatory proteins, further impairing Ras function. In cellular models, the compounds show allele-specific impairment of K-Ras(G12C) function, suggesting a potential therapeutic window for targeted inhibition of K-Ras(G12C) in cancer.