Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor

KRASG12C 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 KRASG12C 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 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 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 KRASG12C-specific inhibitors with promising therapeutic potential. [Display omitted] •ARS-1620, an atropisomeric selective KRASG12C inhibitor with desirable PK•ARS-1620 selectively induces tumor regression in patient-derived tumor models•KRAS dependency is more profound in vivo compared to 2D-monolayer cell culture•ARS-1620 is a valuable pharmacological tool to interrogate KRAS biology in vivo A covalent inhibitor specific for G12C mutant KRAS induces tumor regression in in vivo models.