Journal
ACS CENTRAL SCIENCE
Volume 6, Issue 8, Pages 1367-1375Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acscentsci.0c00411
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Funding
- NIH [R35CA197589, F31CA232477, 5T32GM067543]
- American Cancer Research Professorship
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KRAS is mutated in similar to 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.
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