Novel covalent warhead imparts potent activity against both GDP- and GTP-bound forms of KRAS G12C
The discovery of KRAS G12C inactive state inhibitors represents a significant advancement in the field of precision oncology. While inactive state inhibition shows promise in patients, SWII-binding inhibitors targeting both inactive and active states remain an underdeveloped therapeutic modality. Here, we describe the discovery of KRAS G12C dual inhibitors that bind the SWII allosteric site using a chemically differentiated warhead to covalently modify both KRAS G12C inactive and active states. Co-crystal structures reveal that these inhibitors perturb a key water-mediated hydrogen bonding network and trigger allosteric remodeling of the GTP-bound protein surface and Switch I to prevent binding to downstream effectors. Consistent with simultaneous targeting of the active and inactive state, dual inhibitors provide rapid covalent target engagement and suppression of MAPK signaling. However, KRAS G12C dual and inactive state inhibitors demonstrate similar efficacy in cellular and in vivo models despite faster target inhibition afforded by targeting the active state. Furthermore, KRAS G12C dual and inactive state inhibitors show similar cellular efficacy in the presence of growth factors that drive KRAS, wt NRAS and wt HRAS to the active state. These data provide the first detailed account of targeting the active and inactive state of KRAS and highlight the absence of a mechanistic advantage in the context of prolonged KRAS G12C inhibition and efficacy.