LC-2 is a potent and first-in-class PROTAC capable of degrading endogenous KRAS G12C, with DC50s between 0.25 and 0.76 μM[1]. 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[2].
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
[1]. De Vita E, et al. The Missing Link between (Un)druggable and Degradable KRAS. ACS Cent Sci. 2020;6(8):1281-1284. [2]. Bond MJ, et al. Targeted Degradation of Oncogenic KRASG12C by VHL-Recruiting PROTACs. ACS Cent Sci. 2020;6(8):1367-1375.