Targeted Degradation of Oncogenic KRAS G12C by VHL-Recruiting PROTACs

作者：Michael J. Bond, Ling Chu, Dhanusha A. Nalawansha, Ke Li, Craig M. Crews · 发表于：ACS Central Science · 年份：2020 · DOI：10.1021/acscentsci.0c00411 · 被引用次数：423 · 研究领域：Protein Degradation and Inhibitors、Ubiquitin and proteasome pathways、Multiple Myeloma Research and Treatments

High Resolution Image Download MS PowerPoint Slide KRAS is mutated in ∼20% of human cancers and is one of the most sought-after targets for pharmacological modulation, despite having historically been considered “undruggable.” The discovery of potent covalent inhibitors of the KRAS G12C mutant in recent years has sparked a new wave of interest in small molecules targeting KRAS. While these inhibitors have shown promise in the clinic, we wanted to explore PROTAC-mediated degradation as a complementary strategy to modulate mutant KRAS. Herein, we report the development of LC-2, the first PROTAC capable of degrading endogenous KRAS G12C . 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. LC-2 demonstrates that PROTAC-mediated degradation is a viable option for attenuating oncogenic KRAS levels and downstream signaling in cancer cells.