Targeted Degradation of Oncogenic KRASG12C by VHL-recruiting PROTACs

Abstract

<p>We report the development of LC-2, the first PROTAC capable of degrading endogenous KRAS<sup>G12C</sup>.<sup> </sup> LC-2 covalently binds KRAS<sup>G12C</sup> with a MRTX849 warhead and recruits the E3 ligase VHL, inducing rapid and sustained KRAS<sup>G12C</sup> degradation leading to suppression of MAPK signaling in both homozygous and heterozygous KRAS<sup>G12C</sup> cell lines. LC-2 demonstrates that PROTAC-mediated degradation is a viable option for attenuating oncogenic KRAS levels and downstream signaling in cancer cells.</p>