Targeted Degradation of Oncogenic KRASG12C by VHL-Recruiting PROTACs
Top Cited Papers
- 8 July 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in ACS Central Science
- Vol. 6 (8), 1367-1375
- https://doi.org/10.1021/acscentsci.0c00411
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.Other Versions
Funding Information
- U.S. Department of Health and Human Services (F31CA232477, R35197589)
- American Cancer Society
- U.S. Department of Health and Human Services (5T32GM067543)
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