KRAS G12C PROTAC LC-2 is a potent, selective VHL-Recruiting PROTAC degrader of KRASG12C with DC50 of 0.59 uM and Dmax of 80% in NCI-H2030 cells. LC-2 covalently binds KRASG12C with a MRTX849 warhead and recruits the E3 ligase VHL, inducing rapid and sustained KRASG12C degradation leading to suppression of MAPK signaling in both homozygous and heterozygous KRASG12C cell lines. LC-2 has DC50 values between 0.25 and 0.76 μM as well as Dmax values ranging from ∼75-90% in 5 different KRASG12C cell lines. LC-2 can degrade mutant KRAS in both homozygous and heterozygous cell lines with varying sensitivities to MRTX849. LC-2 modulates Erk signaling in homozygous and heterozygous KRASG12C cell lines.
