LC-2 (PROTAC KRASG12C Degrader-LC-2) is a novel von Hippel-Lindau-based PROTAC degrader of endogenous KRAS G12C with a DC50 between 0.25 and 0.76 μM.LC-2 is a PROTAC that covalently binds KRAS G12C with MRTX849 and recruits the E3 ligase, VH, to induce a rapid and sustained degradation of KRAS G12C. LC-2 inhibits MAPK signaling in pure and heterozygous KRAS G12C cell lines.

LC-2 induces degradation of endogenous KRASG12C in multiple KRAS mutant cancer cell (NCI-H2030, MIA PaCa-2, SW1573, NCI-H23 and NCI-H358 cells) with DC50s between 0.25 and 0.76 μM. LC-2-induced KRASG12C degradation occurs via a bona fide PROTAC mechanism. MIA PaCa-2, NCI-H23, and SW1573 cells are treated with 2.5 μM of LC-2 for 6, 24, 48, and 72 h. In all three cell lines, maximal KRAS degradation occurred within 24 h and was sustained up to 72 h[1].LC-2-induced (2.5 μM; 6-24 hours) KRAS G12C degradation modulates Erk signaling in homozygous and heterozygous KRAS mutant cell lines[1]. Western Blot Analysis[1]Cell Line:MIA PaCa-2 cells and NCI-H23 cells