LC-2 is a potent and first-in-class von Hippel-Lindau -based PROTAC capable of degrading endogenous KRAS G12C , with DC 50 s between 0.25 and 0.76 μM. 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. (Pink: KRas G12C ligand ( HY-130149 ); Blue: VHL ligand ( HY-125845 ); Black: linker).
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