Targeting Multiple KRAS Mutations with High-Affinity Macrocyclic Inhibitors: From Discovery to Preclinical Validation

The RAS Switch-II pockets' discovery enabled targeting a challenging molecular site. Covalent KRAS^G12C inhibitors inspired efforts to find compounds for other KRAS mutations, notably KRAS^G12D and KRAS^G12V. A macrocyclization strategy led to the identification of an exceptionally potent lead compound 12. Highly optimized interactions in the pocket yielded strong affinity against KRAS^G12D and KRAS^G12V, potent inhibition of phospho-ERK in various KRAS mutant cell lines, and tumor regression in mouse xenograft models.