We report the development of LC-2, the first PROTAC capable of degrading endogenous KRASG12C. 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 demonstrates that PROTAC-mediated degradation is a viable option for attenuating oncogenic KRAS levels and downstream signaling in cancer cells.
Targeted Degradation of Oncogenic KRASG12C by VHL-recruiting PROTACs
10 April 2020, Version 1
This content is a preprint and has not undergone peer review at the time of posting.
KRAS Supplemental Figures Final v2