Friday, April 10, 2020

Targeted Degradation of Oncogenic KRASG12C by VHL-recruiting PROTACs [@CraigMCrews]

Bond, Michael J.; Chu, Ling; Nalawansha, Dhanusha A.; Li, Ke; Crews, Craig

ChemRxiv, 2020
DOI: https://doi.org/10.26434/chemrxiv.12091176.v1

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.

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N-Acyl-N-alkyl/aryl Sulfonamide Chemistry Assisted by Proximity for Modification and Covalent Inhibition of Endogenous Proteins in Living Systems

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