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.

中文翻译：

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VHL招募的PROTAC有针对性地降解致癌KRASG12C。

KRAS在约20％的人类癌症中发生了突变，尽管历史上一直被认为是“不可治疗的”，但它却是药理学调节中最受欢迎的靶标之一。近年来，KRAS ^G12C突变体有效的共价抑制剂的发现引发了针对KRAS的小分子的新一波热潮。尽管这些抑制剂已在临床上显示出希望，但我们希望探索PROTAC介导的降解，作为调节突变KRAS的补充策略。在此，我们报告了LC-2的发展，LC-2是第一个能够降解内源性KRAS ^{G12C的PROTAC}。LC-2与MRTX849战斗部共价结合KRAS ^G12C并募集E3连接酶VHL，诱导快速持续的KRAS ^G12C降解导致纯合和杂合KRAS ^G12C细胞系中MAPK信号的抑制。LC-2表明，PROTAC介导的降解是减弱癌细胞中致癌KRAS水平和下游信号传导的可行选择。