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Targeted Degradation of Oncogenic KRASG12C by VHL-Recruiting PROTACs.

ABSTRACT: 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 KRASG12C 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 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.

SUBMITTER: Bond MJ

PROVIDER: S-EPMC7453568 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Targeted Degradation of Oncogenic KRAS<sup>G12C</sup> by VHL-Recruiting PROTACs.

Bond Michael J MJ Chu Ling L Nalawansha Dhanusha A DA Li Ke K Crews Craig M CM

ACS central science 20200708 8

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<sup>G12C</sup> 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. H ...[more]

PMID: 32875077

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