KRASG12C was lately identified to become potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity for an inducible allosteric switch II pocket (S-IIP). Success of the approach requires active cycling of KRASG12C between its active-GTP and inactive-GDP conformations as ease of access from the S-IIP is fixed simply to the GDP-bound condition. This tactic demonstrated achievable for inhibiting mutant KRAS in vitro however, it’s uncertain whether this method would mean in vivo. Here, we describe structure-based design and identification of ARS-1620, a covalent compound rich in potency and selectivity for KRASG12C. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and show monolayer culture formats considerably underestimate KRAS dependency in vivo. This research provides in vivo evidence that mutant KRAS could be selectively targeted and divulges ARS-1620 as representing a brand new generation of KRASG12C-specific inhibitors with promising therapeutic potential.