MRTX849 acid, a derivative of MRTX849, is employed in the synthesis of PROTAC LC-2. LC-2, a potent and pioneering PROTAC, exhibits the ability to efficiently degrade endogenous KRAS G12C with DC50 values ranging between 0.25 and 0.76 μM.

LC-2 facilitates the degradation of KRASG12C in various KRAS mutant cancer cell lines (NCI-H2030, MIA PaCa-2, SW1573, NCI-H23, and NCI-H358) with half-maximal degradation concentrations (DC50s) ranging from 0.25 to 0.76 μM through an authentic PROTAC mechanism. Treatment with 2.5 μM LC-2 for periods of 6 to 72 hours in MIA PaCa-2, NCI-H23, and SW1573 cells demonstrated that the peak degradation of KRAS occurred by 24 hours and persisted for up to 72 hours. Additionally, exposure to LC-2 (2.5 μM; 6-24 hours) leads to modulation of Erk signaling in both homozygous and heterozygous KRAS mutant cell lines.