Targeted Degradation of Oncogenic KRASG12C by VHL-recruiting PROTACs

Abstract

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.