Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor

Summary KRAS G12C was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRAS G12C between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro ; however, it is uncertain whether this approach would translate to  in vivo . Here, we describe structure-based design and identification of ARS-1620, a covalent compound with high potency and selectivity for KRAS G12C . ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo . This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRAS G12C -specific inhibitors with promising therapeutic potential.