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.

KRas (G12C):0.25-0.76 μM (DC50)

LC-2 induces the degradation of endogenous KRASG12C in multiple KRAS mutant cancer cell lines (NCI-H2030, MIA PaCa-2, SW1573, NCI-H23, and NCI-H358) with DC50 values ranging from 0.25 to 0.76 μM via a bona fide PROTAC mechanism. In MIA PaCa-2, NCI-H23, and SW1573 cells treated with 2.5 μM of LC-2 for up to 72 hours, maximal KRAS degradation occurred within 24 hours and was sustained for 72 hours, modulating Erk signaling in homozygous and heterozygous KRAS mutant cell lines, as confirmed by Western Blot Analysis of MIA PaCa-2 and NCI-H23 cells[1].