Targeted Degradation of Oncogenic KRAS G12C by VHL-Recruiting PROTACs.

KRAS is mutated in similar to 20% of human cancers and is one of the most sought-after targets for pharmacological modulation, despite having historically been considered "undruggable." , The discovery of potent covalent inhibitors of the KRAS(G12C) mutant in recent years has sparked a new wave of interest in small molecules targeting KRAS. While these inhibitors have shown promise in the clinic, we wanted to explore PROTAC-mediated degradation as a complementary strategy to modulate mutant KRAS. Herein, we report the development of LC-2, the first PROTAC capable of degrading endogenous KRAS(G12C). LC-2 covalently binds KRAS(G12C) with a MRTX849 warhead and recruits the E3 ligase VHL, inducing rapid and sustained KRAS(G12C) degradation leading to suppression of MAPK signaling in both homozygous and heterozygous KRAS(G12C) cell lines. LC-2 demonstrates that PROTAC-mediated degradation is a viable option for attenuating oncogenic KRAS levels and downstream signaling in cancer cells.